2476582
Hypergravity Provokes a Temporary Reduction in CD4+CD8+ Thymocyte Number and a Persistent Decrease in Medullary Thymic Epithelial Cell Frequency in Mice
Gravity change affects many immunological systems. We investigated the effects of hypergravity (2G) on murine thymic cells. Exposure of mice to 2G for three days reduced the frequency of CD4+CD8+ thymocytes (DP) and mature medullary thymic epithelial cells (mTECs), accompanied by an increment of keratin-5 and keratin-8 double-positive (K5+K8+) TECs that reportedly contain TEC progenitors. Whereas the reduction of DP was recovered by a 14-day exposure to 2G, the reduction of mature mTECs and the increment of K5+K8+ TEC persisted. Interestingly, a surgical lesion of the inner ear’s vestibular apparatus inhibited these hypergravity effects. Quantitative PCR analysis revealed that the gene expression of Aire and RANK that are critical for mTEC function and development were up-regulated by the 3-day exposure and subsequently down-regulated by the 14-day exposure to 2G. Unexpectedly, this dynamic change in mTEC gene expression was independent of the vestibular apparatus. Overall, data suggest that 2G causes a temporary reduction of DP and a persistent reduction of mature mTECs in a vestibular system-dependent manner, and also dysregulates mTEC gene expression without involving the vestibular system. These data might provide insight on the impact of gravity change on thymic functions during spaceflight and living.
35658360
Space flight, microgravity, stress, and immune responses.
Exposure of animals and humans to space flight conditions has resulted in numerous alterations in immunological parameters. Decreases in lymphocyte blastogenesis, cytokine production, and natural killer cell activity have all been reported after space flight. Alterations in leukocyte subset distribution have also been reported after flight of humans and animals in space. The relative contribution of microgravity conditions and stress to the observed results has not been established. Antiorthostatic, hypokinetic, hypodynamic, suspension of rodents and chronic head-down tilt bed-rest of humans have been used to model effects of microgravity on immune responses. After use of these models, some effects of space flight on immune responses, such as decreases in cytokine function, were observed, but others, such as alterations in leukocyte subset distribution, were not observed. These results suggest that stresses that occur during space flight could combine with microgravity conditions in inducing the changes seen in immune responses after space flight. The biological/biomedical significance of space flight induced changes in immune parameters remains to be established. Grant Numbers: NCC2-859, NAG2-933.
45214272
Bioastronautics: the influence of microgravity on astronaut health.
For thousands of years different cultures around the world have assigned their own meaning to the Universe. Through research and technology, we have begun to understand the nature and mysteries of the Cosmos. Last year marked the 40(th) anniversary of our first steps on the Moon, and within two decades it is hoped that humankind will have established a settlement on Mars. Space is a harsh environment, and technological advancements in material science, robotics, power generation, and medical equipment will be required to ensure that astronauts survive interplanetary journeys and settlements. The innovative field of bioastronautics aims to address some of the medical issues astronauts encounter during space travel. Astronauts are faced with several health risks during both short- and long-duration spaceflight due to the hostile environment presented in space. Some of these health problems include bone loss, muscle atrophy, cardiac dysrhythmias, and altered orientation. This review discusses the effects of spaceflight on living organisms, in particular, the specific effects of microgravity on the human body and possible countermeasures to these effects.
18962181
Could spaceflight‐associated immune system weakening preclude the expansion of human presence beyond Earth's orbit?
This year, we celebrate the 40th birthday of the first landing of humans on the moon. By 2020, astronauts should return to the lunar surface and establish an outpost there that will provide a technical basis for future manned missions to Mars. This paper summarizes major constraints associated with a trip to Mars, presents immunological hazards associated with this type of mission, and shows that our current understanding of the immunosuppressive effects of spaceflight is limited. Weakening of the immune system associated with spaceflight is therefore an area that should be considered more thoroughly before we undertake prolonged space voyages.
17978316
Antiorthostatic suspension as a model for the effects of spaceflight on the immune system
We describe the use and appropriateness of antiorthostatic suspension in immunological investigations. This manuscript describes the model and discusses how well data obtained by using the model correlate with spaceflight data. This review concludes with some suggestions for future experiments using antiorthostatic suspension.
40923427
Terrestrial stress analogs for spaceflight associated immune system dysregulation
Recent data indicates that dysregulation of the immune system occurs and persists during spaceflight. Impairment of immunity, especially in conjunction with elevated radiation exposure and limited clinical care, may increase certain health risks during exploration-class deep space missions (i.e. to an asteroid or Mars). Research must thoroughly characterize immune dysregulation in astronauts to enable development of a monitoring strategy and validate any necessary countermeasures. Although the International Space Station affords an excellent platform for on-orbit research, access may be constrained by technical, logistical vehicle or funding limitations. Therefore, terrestrial spaceflight analogs will continue to serve as lower cost, easier access platforms to enable basic human physiology studies. Analog work can triage potential in-flight experiments and thus result in more focused on-orbit studies, enhancing overall research efficiency. Terrestrial space analogs generally replicate some of the physiological or psychological stress responses associated with spaceflight. These include the use of human test subjects in a laboratory setting (i.e. exercise, bed rest, confinement, circadian misalignment) and human remote deployment analogs (Antarctica winterover, undersea, etc.) that incorporate confinement, isolation, extreme environment, physiological mission stress and disrupted circadian rhythms. While bed rest has been used to examine the effects of physical deconditioning, radiation and microgravity may only be simulated in animal or microgravity cell culture (clinorotation) analogs. This article will characterize the array of terrestrial analogs for spaceflight immune dysregulation, the current evidence base for each, and interpret the analog catalog in the context of acute and chronic stress.
6360892
Hindlimb unloading rodent model : technical aspects
[PDF]  [Full Text]  [Abstract] , June, 2010; 298 (6): C1489-C1500. Am J Physiol Cell Physiol Zhi-Bin Yu and Jin Ma Man-Jiang Xie, Yu-Guang Ma, Fang Gao, Yun-Gang Bai, Jiu-Hua Cheng, Yao-Ming Chang, smooth muscle cells in simulated microgravity rats channel is associated with increased apoptosis of cerebrovascular Ca Activation of BK [PDF]  [Full Text]  [Abstract] , August, 2010; 109 (2): 350-357. J Appl Physiol and Mary L. Bouxsein Erika B. Wagner, Nicholas P. Granzella, Hiroaki Saito, Dava J. Newman, Laurence R. Young musculoskeletal loading Partial weight suspension: a novel murine model for investigating adaptation to reduced [PDF]  [Full Text]  [Abstract] , November, 15 2010; 588 (22): 4579-4591. J Physiol Desplanches and Olivier Birot Emilie Roudier, Charlotte Gineste, Alexandra Wazna, Kooroush Dehghan, Dominique type-specific dynamic process Angio-adaptation in unloaded skeletal muscle: new insights into an early and muscle [PDF]  [Full Text]  [Abstract] , December, 2010; 299 (6): R1572-R1581. Am J Physiol Regul Integr Comp Physiol Janna R. Jackson, Michael J. Ryan, Yanlei Hao and Stephen E. Alway following muscle disuse in the gastrocnemius muscles of young and old rats Mediation of endogenous antioxidant enzymes and apoptotic signaling by resveratrol [PDF]  [Full Text]  [Abstract] , February, 2011; 300 (2): R408-R417. Am J Physiol Regul Integr Comp Physiol Erwan Dupont, Caroline Cieniewski-Bernard, Bruno Bastide and Laurence Stevens without preventing soleus atrophy and restores slow phenotype through ERK Electrostimulation during hindlimb unloading modulates PI3K-AKT downstream targets
36844926
Animal models for the study of the effects of spaceflight on the immune system.
Animal models have been used to determine the effects of spaceflight on the immune system. Rats and rhesus monkeys have been the primary animals used for actual space flight studies, but mice have also been utilized for studies in ground-based models. The primary ground based model used has been hindlimb unloading of rodents, which is similar to the chronic bed-rest model for humans. A variety of immune responses have been shown to be modified when animals are hindlimb unloaded. These results parallel those observed when animals are flown in space. In general, immune responses are depressed in animals maintained in the hindlimb unloading model or flown in space. These results raise the possibility that spaceflight could result in decreased resistance to infection in animals.
24011757
Responses across the gravity continuum: hypergravity to microgravity.
In response to hypergravity, it appears that the larger the animal, the greater the response, if present. Therefore, the response of a rat exceeds that of a mouse in the same hypergravity environment. When investigated in the microgravity environment of space flight, this appears to hold true. The lack of definitive data obtained in space for either species makes the extrapolation of the continuum to levels below Earth-gravity problematic. However, in systems where responses are detected for both space flight and acceleration by centrifugation, a gravitational continuum is present supporting the "principle of continuity". For those and similar systems, it appears that the use of hypergravity could be used to predict responses to space flight.
29055588
The unresponsiveness of the immune system of the rat to hypergravity.
The immune response in rats exposed to simulated hypergravity (2.1 G and 3.1 G) by chronic centrifugation was assessed. Rats were immunized with sheep red blood cells (SRBC), either on the day of initial exposure to hypergravity (hyper-G), or after being centrifuged for 28 d and remaining on the centrifuge thereafter. Pair-fed and ad libitum fed noncentrifuged controls were used. Although there were some alterations in leukocyte counts, hyper-G did not systematically affect the primary or secondary anti-SRBC response, hematocrits, or the sizes of the liver, spleen, kidneys, thymus, or adrenal glands. The immune system is thus remarkably homeostatic under hypergravity conditions which do affect other physiologic parameters.
30894518
Hypergravity-induced immunomodulation in a rodent model: lymphocytes and lymphoid organs.
The major goal of this study was to quantify changes in lymphoid organs and cells over time due to centrifugation-induced hypergravity. C57BL/6 mice were exposed to 1, 2 and 3 G and the following assays were performed on days 1, 4, 7, 10, and 21: spleen, thymus, lung, and liver masses; total leukocyte, lymphocyte, monocyte/macrophage, and granulocyte counts; level of splenocyte apoptosis; enumeration of CD3+ T, CD3+/CD4+ T helper, CD3+/CD8+ T cytotoxic, B220+ B, and NK1.1+ natural killer cells; and quantification of cells expressing CD25, CD69, and CD71 activation markers. The data show that increased gravity resulted in decreased body, spleen, thymus, and liver, but not lung, mass. Significant reductions were noted in all three major leukocyte populations (lymphocytes, granulocytes, monocyte/macrophages) [correction of macrphages] with increased gravity; persistent depletion was noted in blood but not spleen. Among the various lymphocyte populations, the CD3+/CD8+ T cells and B220+ B cells were the most affected and NK1.1+ NK cells the least affected. Overall, the changes were most evident during the first week, with a greater influence noted for cells in the spleen. A linear relationship was found between some of the measurements and the level of gravity, especially on day 4. These findings indicate that hypergravity profoundly alters leukocyte number and distribution in a mammalian model and that some aberrations persisted throughout the three weeks of the study. In certain cases, the detected changes were similar to those observed after whole-body irradiation. In future investigations we hope to combine hypergravity with low-dose rate irradiation and immune challenge.
25774158
Stress response and humoral immune system alterations related to chronic hypergravity in mice
Spaceflights are known to induce stress and immune dysregulation. Centrifugation, as hindlimb unloading, is a good ground based-model to simulate altered gravity which occurs during space missions. The aim of this study was to investigate the consequences of a long-term exposure to different levels of hypergravity on the stress response and the humoral immunity in a mouse model. For this purpose, adult C57Bl/6J male mice were subjected for 21 days either to control conditions or to 2G or 3G acceleration gravity forces. Corticosterone level and anxiety behavior revealed a stress response which was associated with a decrease of body weight, after 21-day of centrifugation at 3G but not at 2G. Spleen lymphocyte lipopolysaccharide (LPS) responsiveness was diminished by 40% in the 2G group only, whereas a decrease was noted when cells were stimulated with concanavalin A for both 2G and 3G groups (about 25% and 20%, respectively) compared to controls. Pro-inflammatory chemokines (MCP-1 and IP-10) and Th1 cytokines (IFNγ and IL2) were slightly decreased in the 2G group and strongly decreased in the 3G mouse group. Regarding Th2 cytokines (IL4, IL5) no further significant modification was observed, whereas the immunosuppressive cytokine IL10 was slightly increased in the 3G mice. Finally, serum IgG concentration was twice higher whereas IgA concentration was slightly increased (about 30%) and IgM were unchanged in 2G mice compared to controls. No difference was observed in the 3G group with these isotypes. Consequently, functional immune dysregulations and stress responses were dependent of the gravity level.
28690556
Microgravity: the immune response and bone
Summary:  Exposure to microgravity during space flight affects almost all human physiological systems. The affected systems that are of key importance to human space exploration are the musculoskeletal, neurovestibular, and cardiovascular systems. However, alterations in the immune and endocrine functions have also been described. Bone loss has been shown to be site specific, predominantly in the weight‐bearing regions of the legs and lumbar spine. This phenomenon has been attributed to a reduction in bone formation resulting from a decrease in osteoblastic function and an increase in osteoclastic resorption. In order to examine the effects of microgravity on cellular function here on earth, several ground‐based studies have been performed using different systems to model microgravity. Our studies have shown that modeled microgravity (MMG) inhibits the osteoblastic differentiation of human mesenchymal stem cells (hMSCs) while increasing their adipogenic differentiation. Here, we discuss the potential molecular mechanisms that could be altered in microgravity. In particular, we examine the role of RhoA kinase in maintaining the formation of actin stress fibers and the expression of nitric oxide synthase under MMG conditions. These proposed mechanisms, although only examined in hMSCs, could be part of a global response to microgravity that ultimately alters human physiology.
21599514
Plasma and blood volume in space.
Body fluid regulation is affected by gravity. The primary mechanisms of the etiology of hypovolemia found in simulation studies on earth and after space flight are different. The increased diuresis after increase of central blood volume postulated by Henry Gauer could not be found. Based on recent findings, new hypotheses about fluid volume regulation during space flight have emerged. The reduced blood volume in space is the result of 1) a negative balance of decreased fluid intake and smaller reduction of urine output; 2) fast fluid shifts from the intravascular to interstitial space as the result of lower transmural pressure after reduced compression of all tissue by gravitational forces especially of the thorax cage; and 3) fluid shifts from intravascular to muscle interstitial space because of less muscle tone required to maintain body posture. Additionally, loss of erythrocytes reduces blood volume. The attenuated diuresis during space flight can be explained by increased retention after stress-mediated sympathetic activation during initial phase of space flight, stimulation caused by reduced red cell mass, and activation after fast blood volume contraction. Additionally, the relation between plasma osmolarity and vasopressin release might be disturbed in microgravity.
9621529
Thymic generation and regeneration
Summary:  The thymus is a complex epithelial organ in which thymocyte development is dependent upon the sequential contribution of morphologically and phenotypically distinct stromal cell compartments. It is these microenvironments that provide the unique combination of cellular interactions, cytokines, and chemokines to induce thymocyte precursors to undergo a differentiation program that leads to the generation of functional T cells. Despite the indispensable role of thymic epithelium in the generation of T cells, the mediators of this process and the differentiation pathway undertaken by the primordial thymic epithelial cells are not well defined. There is a lack of lineage‐specific cell‐surface‐associated markers, which are needed to characterize putative thymic epithelial stem cell populations. This review explores the role of thymic stromal cells in T‐cell development and thymic organogenesis, as well as the molecular signals that contribute to the growth and expansion of primordial thymic epithelial cells. It highlights recent advances in these areas, which have allowed for a lineage relationship amongst thymic epithelial cell subsets to be proposed. While many fundamental questions remain to be addressed, collectively these works have broadened our understanding of how the thymic epithelium becomes specialized in the ability to support thymocyte differentiation. They should also facilitate the development of novel, rationally based therapeutic strategies for the regeneration and manipulation of thymic function in the treatment of many clinical conditions in which defective T cells have an important etiological role.
33460533
Thymic epithelial cells: working class heroes for T cell development and repertoire selection.
The thymus represents an epithelial-mesenchymal tissue, anatomically structured into discrete cortical and medullary regions that contain phenotypically and functionally distinct stromal cells, as well as thymocytes at defined stages of maturation. The stepwise progression of thymocyte development seems to require serial migration through these distinct thymic regions, where interactions with cortical thymic epithelial cell (cTEC) and medullary thymic epithelial cell (mTEC) subsets take place. Recent work on TEC subsets provides insight into T cell development and selection, such as the importance of tumour necrosis factor (TNF) receptor superfamily members in thymus medulla development, and the specialised antigen processing/presentation capacity of the thymic cortex for positive selection. Here, we summarise current knowledge on the development and function of the thymic microenvironment, paying particular attention to the cortical and medullary epithelial compartments.
13585200
Positive and negative selection of the T cell repertoire: what thymocytes see (and don't see)
The fate of developing T cells is specified by the interaction of their antigen receptors with self-peptide–MHC complexes that are displayed by thymic antigen-presenting cells (APCs). Various subsets of thymic APCs are strategically positioned in particular thymic microenvironments and they coordinate the selection of a functional and self-tolerant T cell repertoire. In this Review, we discuss the different strategies that these APCs use to sample and process self antigens and to thereby generate partly unique, 'idiosyncratic' peptide–MHC ligandomes. We discuss how the particular composition of the peptide–MHC ligandomes that are presented by specific APC subsets not only shapes the T cell repertoire in the thymus but may also indelibly imprint the behaviour of mature T cells in the periphery.
32906513
A central role for central tolerance.
Recent elucidation of the role of central tolerance in preventing organ-specific autoimmunity has changed our concepts of self/nonself discrimination. This paradigmatic shift is largely attributable to the discovery of promiscuous expression of tissue-restricted self-antigens (TRAs) by medullary thymic epithelial cells (mTECs). TRA expression in mTECs mirrors virtually all tissues of the body, irrespective of developmental or spatio-temporal expression patterns. This review summarizes current knowledge on the cellular and molecular regulation of TRA expression in mTECs, outlines relevant mechanisms of antigen presentation and modes of tolerance induction, and discusses implications for the pathogenesis of autoimmune diseases and other biological processes such as fertility, pregnancy, puberty, and tumor defense.
206547234
Aire-Dependent Thymic Development of Tumor-Associated Regulatory T Cells
On the Origin of Tumor Tregs The tumor microenvironment is often seeded with regulatory T cells (Tregs), which inhibit antitumor immunity. Using mice with genetically driven prostate cancer, Malchow et al. (p. 1219; see the Perspective by Joshi and Jacks) found a population of Tregs that were enriched in the prostate of tumor-bearing mice. Surprisingly, these cells were also present in female mice and were found to be specific, not for a tumor-specific antigen, but rather for an antigen normally expressed in the prostate. Prostate antigen–specific Tregs arose in the thymus and their selection was dependent on Aire, a protein that drives the expression of tissue-specific antigens in the thymus. Thus, Tregs that seed tumors likely arise in the thymus, are not necessarily tumor-specific, and are recruited and/or expand in an organ when a tumor arises. Prostate tumors in mice recruit thymus-derived regulatory T cells that are specific for tissue autoantigens. [Also see Perspective by Joshi and Jacks] Despite considerable interest in the modulation of tumor-associated Foxp3+ regulatory T cells (Tregs) for therapeutic benefit, little is known about the developmental origins of these cells and the nature of the antigens that they recognize. We identified an endogenous population of antigen-specific Tregs (termed MJ23 Tregs) found recurrently enriched in the tumors of mice with oncogene-driven prostate cancer. MJ23 Tregs were not reactive to a tumor-specific antigen but instead recognized a prostate-associated antigen that was present in tumor-free mice. MJ23 Tregs underwent autoimmune regulator (Aire)–dependent thymic development in both male and female mice. Thus, Aire-mediated expression of peripheral tissue antigens drives the thymic development of a subset of organ-specific Tregs, which are likely coopted by tumors developing within the associated organ.
25738896
Aire deficiency promotes TRP-1-specific immune rejection of melanoma.
The thymic transcription factor autoimmune regulator (Aire) prevents autoimmunity in part by promoting expression of tissue-specific self-antigens, which include many cancer antigens. For example, AIRE-deficient patients are predisposed to vitiligo, an autoimmune disease of melanocytes that is often triggered by efficacious immunotherapies against melanoma. Therefore, we hypothesized that Aire deficiency in mice may elevate immune responses to cancer and provide insights into how such responses might be triggered. In this study, we show that Aire deficiency decreases thymic expression of TRP-1 (TYRP1), which is a self-antigen in melanocytes and a cancer antigen in melanomas. Aire deficiency resulted in defective negative selection of TRP-1-specific T cells without affecting thymic numbers of regulatory T cells. Aire-deficient mice displayed elevated T-cell immune responses that were associated with suppression of melanoma outgrowth. Furthermore, transplantation of Aire-deficient thymic stroma was sufficient to confer more effective immune rejection of melanoma in an otherwise Aire wild-type host. Together, our work showed how Aire deficiency can enhance immune responses against melanoma and how manipulating TRP-1-specific T-cell negative selection may offer a logical strategy to enhance immune rejection of melanoma.
6503263
Limitation of immune tolerance–inducing thymic epithelial cell development by Spi-B–mediated negative feedback regulation
Akiyama et al. show that transcription factor Spi-B is up-regulated by RANKL to trigger mTEC differentiation. Osteoprotegerin is also induced by this signaling pathway and acts as a negative feedback loop to attenuate mTEC development and thymic T reg cells.
43844251
Molecular control over thymic involution: From cytokines and microRNA to aging and adipose tissue
The thymus is the primary organ for T‐cell differentiation and maturation. Unlike other major organs, the thymus is highly dynamic, capable of undergoing multiple rounds of almost complete atrophy followed by rapid restoration. The process of thymic atrophy, or involution, results in decreased thymopoiesis and emigration of naïve T cells to the periphery. Multiple processes can trigger transient thymic involution, including bacterial and viral infection(s), aging, pregnancy and stress. Intense investigations into the mechanisms that underlie thymic involution have revealed diverse cellular and molecular mediators, with elaborate control mechanisms. This review outlines the disparate pathways through which involution can be mediated, from the transient infection‐mediated pathway, tightly controlled by microRNA, to the chronic changes that occur through aging.
16941167
Cytokines, leptin, and stress‐induced thymic atrophy
Thymopoiesis is essential for development and maintenance of a robust and healthy immune system. Acute thymic atrophy is a complication of many infections, environmental stressors, clinical preparative regimens, and cancer treatments used today. This undesirable sequela can decrease host ability to reconstitute the peripheral T cell repertoire and respond to new antigens. Currently, there are no treatments available to protect against acute thymic atrophy or accelerate recovery, thus leaving the immune system compromised during acute stress events. Several useful murine models are available for mechanistic studies of acute thymic atrophy, including a sepsis model of endotoxin‐induced thymic involution. We have identified the IL‐6 cytokine gene family members (i.e., leukemia inhibitory factor, IL‐6, and oncostatin M) as thymosuppressive agents by the observation that they can acutely involute the thymus when injected into a young, healthy mouse. We have gone on to explore the role of thymosuppressive cytokines and specifically defined a corticosteroid‐dependent mechanism of action for the leukemia inhibitory factor in acute thymic atrophy. We also have identified leptin as a novel, thymostimulatory agent that can protect against endotoxin‐induced acute thymic atrophy. This review will highlight mechanisms of stress‐induced thymic involution and focus on thymosuppressive agents involved in atrophy induction and thymostimulatory agents that may be exploited for therapeutic use.
31038199
Getting back at nature: understanding thymic development and overcoming its atrophy.
T cell development is a complex and tightly regulated process involving reciprocal interactions between the thymic stroma and differentiating thymocytes. Normal thymic function is critical for immunity and microenvironmental defects predispose to dysregulation in the T cell compartment. Thymic structure and function are also severely damaged by chemotherapy and pre-transplant conditioning. Furthermore, poor immune competence with ageing is closely linked to thymic atrophy. Overcoming such thymic defects would have immediate application in many diseases, especially the recovery of cancer patients from cytotoxic treatment. Reversing the thymus ageing process via inhibition of atrophic factors such as sex steroids or administration of thymopoietic growth factors is one possible approach. Moreover, it is becoming clear a common thymic epithelial progenitor exists, raising the possibility for de novo thymus generation using emerging stem cell and tissue engineering technologies. Achievement of this goal will open up many avenues for the application of thymus-based immune rejuvenation and manipulation.
34843872
Effect of a 22-day space flight on the lymphoid organs of rats.
The effect of a 22-d space flight on the lymphoid organs of rats has been investigated. It has been shown that the flight leads to hypoplasia of lymphoid organs, the spleen and thymus weight decreasing very noticeably. Histological, morphometric, and cytological examinations have demonstrated that hypoplasia of the spleen occurs due to a reduction of the number of lymphocytes and erythroid cells and hypoplasia of the thymus and lymph nodes due to a decrease of the lymphocyte number. Changes found in the lymphoid organs of the flight rats are reversible and the structure of lymphoid organs recovers 27 d postflight. Pathogenetic mechanisms of the changes developing in lymphoid organs of rats under the influence of space flight are discussed. The animal data are compared with the results of postflight medical examinations of astronauts.
2638338
Effects of spaceflight on innate immune function and antioxidant gene expression.
Spaceflight conditions have a significant impact on a number of physiological functions due to psychological stress, radiation, and reduced gravity. To explore the effect of the flight environment on immunity, C57BL/6NTac mice were flown on a 13-day space shuttle mission (STS-118). In response to flight, animals had a reduction in liver, spleen, and thymus masses compared with ground (GRD) controls (P < 0.005). Splenic lymphocyte, monocyte/macrophage, and granulocyte counts were significantly reduced in the flight (FLT) mice (P < 0.05). Although spontaneous blastogenesis of splenocytes in FLT mice was increased, response to lipopolysaccharide (LPS), a B-cell mitogen derived from Escherichia coli, was decreased compared with GRD mice (P < 0.05). Secretion of IL-6 and IL-10, but not TNF-alpha, by LPS-stimulated splenocytes was increased in FLT mice (P < 0.05). Finally, many of the genes responsible for scavenging reactive oxygen species were upregulated after flight. These data indicate that exposure to the spaceflight environment can increase anti-inflammatory mechanisms and change the ex vivo response to LPS, a bacterial product associated with septic shock and a prominent Th1 response.
1012303
Changes in Mouse Thymus and Spleen after Return from the STS-135 Mission in Space
Our previous results with flight (FLT) mice showed abnormalities in thymuses and spleens that have potential to compromise immune defense mechanisms. In this study, the organs were further evaluated in C57BL/6 mice after Space Shuttle Atlantis returned from a 13-day mission. Thymuses and spleens were harvested from FLT mice and ground controls housed in similar animal enclosure modules (AEM). Organ and body mass, DNA fragmentation and expression of genes related to T cells and cancer were determined. Although significance was not obtained for thymus mass, DNA fragmentation was greater in the FLT group (P<0.01). Spleen mass alone and relative to body mass was significantly decreased in FLT mice (P<0.05). In FLT thymuses, 6/84 T cell-related genes were affected versus the AEM control group (P<0.05; up: IL10, Il18bp, Il18r1, Spp1; down: Ccl7, IL6); 15/84 cancer-related genes had altered expression (P<0.05; up: Casp8, FGFR2, Figf, Hgf, IGF1, Itga4, Ncam1, Pdgfa, Pik3r1, Serpinb2, Sykb; down: Cdc25a, E2F1, Mmp9, Myc). In the spleen, 8/84 cancer-related genes were affected in FLT mice compared to AEM controls (P<0.05; up: Cdkn2a; down: Birc5, Casp8, Ctnnb1, Map2k1, Mdm2, NFkB1, Pdgfa). Pathway analysis (apoptosis signaling and checkpoint regulation) was used to map relationships among the cancer–related genes. The results showed that a relatively short mission in space had a significant impact on both organs. The findings also indicate that immune system aberrations due to stressors associated with space travel should be included when estimating risk for pathologies such as cancer and infection and in designing appropriate countermeasures. Although this was the historic last flight of NASA’s Space Shuttle Program, exploration of space will undoubtedly continue.
23188125
Lymphatic tissue changes in rats flown on Spacelab Life Sciences-2.
Thymus, spleen, inguinal lymph node, and bone marrow specimens from rats flown on the 14-day Spacelab Life Sciences-2 mission were examined after staining of tissue sections. The primary observation was a transient retrogressive change in lymphatic tissues in the rats within a few hours after landing. There was a diffuse increase in tingible body-containing macrophages in the cortex of the thymus, thymus-dependent areas of the splenic white pulp, and inguinal lymph node. This was not observed 9 days after recovery. The in situ labeling of fragmented DNA strands catalyzed by exogenous terminal deoxynucleotidyltransferase (TdT) with ApopTag reagents (Oncor, Gaithersburg, MD) inside the tingible body-containing macrophages indicated that the process was one of apoptosis. No increase in tingible body macrophage activity was noted in thymus and spleen tissue obtained from rats in flight on flight day 13. The reaction to gravitational stress from readaptation to 1 G is the most likely explanation of the transient retrogressive change in lymphatic tissues.
22311091
The hindlimb unloading rat model: literature overview, technique update and comparison with space flight data.
The hindlimb unloading rodent model is used extensively to study the response of many physiological systems to certain aspects of space flight, as well as to disuse and recovery from disuse for Earth benefits. This chapter describes the evolution of hindlimb unloading, and is divided into three sections. The first section examines the characteristics of 1064 articles using or reviewing the hindlimb unloading model, published between 1976 and April 1, 2004. The characteristics include number of publications, journals, countries, major physiological systems, method modifications, species, gender, genetic strains and ages of rodents, experiment duration, and countermeasures. The second section provides a comparison of results between space flown and hindlimb unloading animals from the 14-day Cosmos 2044 mission. The final section describes modifications to hindlimb unloading required by different experimental paradigms and a method to protect the tail harness for long duration studies. Hindlimb unloading in rodents has enabled improved understanding of the responses of the musculoskeletal, cardiovascular, immune, renal, neural, metabolic, and reproductive systems to unloading and/or to reloading on Earth with implications for both long-duration human space flight and disuse on Earth.
248276
Identification and characterization of thymic epithelial progenitor cells.
T cell differentiation and repertoire selection depend critically on several distinct thymic epithelial cell types, whose lineage relationships are unclear. We have investigated these relationships via functional analysis of the epithelial populations within the thymic primordium. Here, we show that mAbs MTS20 and MTS24 identify a population of cells that, when purified and grafted ectopically, can differentiate into all known thymic epithelial cell types, attract lymphoid progenitors, and support CD4(+) and CD8(+) T cell development in nude mice. In contrast, other epithelial populations in the thymic primordium can fulfill none of these functions. These data establish that the MTS20(+)24(+) population is sufficient to generate a functional thymus in vivo and thus argue strongly that all thymic epithelial cell types derive from a common progenitor cell.
24670507
Generation of a complete thymic microenvironment by MTS24+ thymic epithelial cells
The epithelial component of the thymic microenvironment is indispensable for the generation of T lymphocytes. Although the heterogeneity of this epithelium is well documented, little is known about precursor-progeny relationships between distinct thymic epithelial lineages. Here we characterized a thymic epithelial cell subpopulation identified by the cell surface glycoprotein MTS24. These cells contained epithelial progenitor cells that were competent and sufficient to fully reconstitute the complex thymic epithelial microenvironment that supported normal T cell development.
7786859
Identification of Novel Thymic Epithelial Cell Subsets Whose Differentiation Is Regulated by RANKL and Traf6
Thymic epithelial cells (TECs) are critical for the normal development and function of the thymus. Here, we examined the developmental stages of TECs using quantitative assessment of the cortical and medullary markers Keratin 5 and Keratin 8 (K5 and K8) respectively, in normal and gain/loss of function mutant animals. Gain of function mice overexpressed RANKL in T cells, whereas loss of function animals lacked expression of Traf6 in TECs (Traf6ΔTEC). Assessment of K5 and K8 expression in conjunction with other TEC markers in wild type mice identified novel cortical and medullary TEC populations, expressing different combinations of these markers. RANKL overexpression led to expansion of all medullary TECs (mTECs) and enlargement of the thymic medulla. This in turn associated with a block in thymocyte development and loss of CD4+CD8+, CD4+ and CD8+ thymocytes. In contrast, Traf6 deletion inhibited the production of most TEC populations including cortical TECs (cTECs), defined by absence of UEA-1 binding and LY51 expression, but had no apparent effect on thymocyte development. These results reveal a large degree of heterogeneity within the TEC compartment and the existence of several populations exhibiting concomitant expression of cortical, medullary and epithelial markers and whose production is regulated by RANKL and Traf6.
23013883
Roles of baroreflex and vestibulosympathetic reflex in controlling arterial blood pressure during gravitational stress in conscious rats.
Gravity acts on the circulatory system to decrease arterial blood pressure (AP) by causing blood redistribution and reduced venous return. To evaluate roles of the baroreflex and vestibulosympathetic reflex (VSR) in maintaining AP during gravitational stress, we measured AP, heart rate (HR), and renal sympathetic nerve activity (RSNA) in four groups of conscious rats, which were either intact or had vestibular lesions (VL), sinoaortic denervation (SAD), or VL plus SAD (VL + SAD). The rats were exposed to 3 G in dorsoventral axis by centrifugation for 3 min. In rats in which neither reflex was functional (VL + SAD group), RSNA did not change, but the AP showed a significant decrease (-8 +/- 1 mmHg vs. baseline). In rats with a functional baroreflex, but no VSR (VL group), the AP did not change and there was a slight increase in RSNA (25 +/- 10% vs. baseline). In rats with a functional VSR, but no baroreflex (SAD group), marked increases in both AP and RSNA were observed (AP 31 +/- 6 mmHg and RSNA 87 +/- 10% vs. baseline), showing that the VSR causes an increase in AP in response to gravitational stress; these marked increases were significantly attenuated by the baroreflex in the intact group (AP 9 +/- 2 mmHg and RSNA 38 +/- 7% vs. baseline). In conclusion, AP is controlled by the combination of the baroreflex and VSR. The VSR elicits a huge pressor response during gravitational stress, preventing hypotension due to blood redistribution. In intact rats, this AP increase is compensated by the baroreflex, resulting in only a slight increase in AP.
207421123
Ablation and Regeneration of Tolerance-Inducing Medullary Thymic Epithelial Cells after Cyclosporine, Cyclophosphamide, and Dexamethasone Treatment1
Immunosuppressive drugs and cytotoxic chemotherapy agents are designed to kill or suppress autoreactive, alloaggressive, or hyperinflammatory T cells, or disseminated malignancies. However, they also cause severe immunological side effects ranging from interrupted thymopoiesis and general immunodeficiency to, paradoxically, autoimmunity. Consistent with the cross-talk between thymocytes and stromal cells, we now show that these common therapeutic agents have major effects on murine thymic epithelial cells (TEC), crucially required to rebuild immunity posttreatment. We show that the immunosuppressant cyclosporine A, which has been linked to a thymus-dependent autoimmune syndrome in some patients, causes extensive loss of autoimmune regulator (Aire+) tolerance-inducing MHC class IIhigh medullary TEC (mTEChigh). Post-cyclosporine A, Aire expression was restored within 7 days. Full recovery of the mTEChigh subset occurred within 10 days and was linked to a decrease in a relatively resistant MHC class IIlow mTEC subset (mTEClow), consistent with a previously described precursor-product relationship. Cyclophosphamide and dexamethasone caused more extensive ablation of thymocytes and stromal cells but again severely depleted tolerance-inducing mTEChigh. Together, these data show that Aire+ mTECs are highly sensitive to damage and that mTEC regeneration follows a conserved pattern regardless of the treatment regimen used.
24335554
Multilineage potential and self-renewal define an epithelial progenitor cell population in the adult thymus.
Thymic epithelial cells (TECs) are critical for T cell development and self-tolerance but are gradually lost with age. The existence of thymic epithelial progenitors (TEPCs) in the postnatal thymus has been inferred, but their identity has remained enigmatic. Here, we assessed the entire adult TEC compartment in order to reveal progenitor capacity is retained exclusively within a subset of immature thymic epithelium displaying several hallmark features of stem/progenitor function. These adult TEPCs generate mature cortical and medullary lineages in a stepwise fashion, including Aire+ TEC, within fetal thymus reaggregate grafts. Although relatively quiescent in vivo, adult TEPCs demonstrate significant in vitro colony formation and self-renewal. Importantly, 3D-cultured TEPCs retain their capacity to differentiate into cortical and medullary TEC lineages when returned to an in vivo thymic microenvironment. No other postnatal TEC subset exhibits this combination of properties. The characterization of adult TEPC will enable progress in understanding TEC biology in aging and regeneration.
663881
Regeneration of the adult thymus is preceded by the expansion of K5+K8+ epithelial cell progenitors and by increased expression of Trp63, cMyc and Tcf3 transcription factors in the thymic stroma.
Studies of HIV-1-infected individuals on anti-retroviral therapies and of patients receiving lymphoablating treatments indicate that the thymus retains restorative capacity even in adults. The contributions of the thymic epithelial cells (TECs) to the regeneration of the thymus and the identity of epithelial cell progenitors were evaluated in murine models of transient thymic atrophy followed by a complete regeneration. Using microarray approach, we analyzed the pattern of gene expression in TECs sorted from mice that were depleted of thymocytes by steroid treatment or by irradiation. The initial analysis identified significant increases in the mRNA for cMyc, Trp63 and Tcf3 transcription factors known to be expressed in early epithelial cell progenitors in tissues other than the thymus. Immunohistochemistry showed that in involuted thymuses, the cMyc and Trp63 proteins were expressed in a subset of cortical thymic epithelial cells (cTECs) that were keratin 5 positive (K5(+)), typifying cTEC precursors. Importantly, confocal microscopy established that epithelial cells with the phenotype of putative TEC progenitors (i.e. K5(+)K8(+)) expressed the Trp63 protein and confirmed that K5(+)K8(+) TEC progenitors expanded significantly during atrophy and prior to the thymic regeneration. Thus, our data demonstrated for the first time that critical steps in the recovery of the adult thymus include expansion of TEC progenitors and elevated expression of Trp63, cMyc and Tcf3 transcription factors in the thymic stroma. These results suggest that TEC progenitors could be reactivated in the adult thymus and, therefore, reactivation of TEC progenitors could provide a new approach for thymic reconstitution.
7306123
TNF receptor family signaling in the development and functions of medullary thymic epithelial cells
Thymic epithelial cells (TECs) provide the microenvironment required for the development of T cells in the thymus. A unique property of medullary thymic epithelial cells (mTECs) is their expression of a wide range of tissue-restricted self-antigens, critically regulated by the nuclear protein AIRE, which contributes to the selection of the self-tolerant T cell repertoire, thereby suppressing the onset of autoimmune diseases. The TNF receptor family (TNFRF) protein receptor activator of NF-κB (RANK), CD40 and lymphotoxin β receptor (LtβR) regulate the development and functions of mTECs. The engagement of these receptors with their specific ligands results in the activation of the NF-κB family of transcription factors. Two NF-κB activation pathways, the classical and non-classical pathways, promote the development of mature mTECs induced by these receptors. Consistently, TNF receptor-associated factor (TRAF6), the signal transducer of the classical pathway, and NF-κB inducing kinase (NIK), the signal transducer of the non-classical pathway, are essential for the development of mature mTECs. This review summarizes the current understanding of how the signaling by the TNF receptor family controls the development and functions of mTEC.
3952288
RANK signals from CD4+3− inducer cells regulate development of Aire-expressing epithelial cells in the thymic medulla
Aire-expressing medullary thymic epithelial cells (mTECs) play a key role in preventing autoimmunity by expressing tissue-restricted antigens to help purge the emerging T cell receptor repertoire of self-reactive specificities. Here we demonstrate a novel role for a CD4+3− inducer cell population, previously linked to development of organized secondary lymphoid structures and maintenance of T cell memory in the functional regulation of Aire-mediated promiscuous gene expression in the thymus. CD4+3− cells are closely associated with mTECs in adult thymus, and in fetal thymus their appearance is temporally linked with the appearance of Aire+ mTECs. We show that RANKL signals from this cell promote the maturation of RANK-expressing CD80−Aire− mTEC progenitors into CD80+Aire+ mTECs, and that transplantation of RANK-deficient thymic stroma into immunodeficient hosts induces autoimmunity. Collectively, our data reveal cellular and molecular mechanisms leading to the generation of Aire+ mTECs and highlight a previously unrecognized role for CD4+3−RANKL+ inducer cells in intrathymic self-tolerance.
205410399
The tumor necrosis factor family receptors RANK and CD40 cooperatively establish the thymic medullary microenvironment and self-tolerance.
Medullary thymic epithelial cells (mTECs) establish T cell self-tolerance through the expression of autoimmune regulator (Aire) and peripheral tissue-specific self-antigens. However, signals underlying mTEC development remain largely unclear. Here, we demonstrate crucial regulation of mTEC development by receptor activator of NF-kappaB (RANK) and CD40 signals. Whereas only RANK signaling was essential for mTEC development during embryogenesis, in postnatal mice, cooperation between CD40 and RANK signals was required for mTEC development to successfully establish the medullary microenvironment. Ligation of RANK or CD40 on fetal thymic stroma in vitro induced mTEC development in a tumor necrosis factor-associated factor 6 (TRAF6)-, NF-kappaB inducing kinase (NIK)-, and IkappaB kinase beta (IKKbeta)-dependent manner. These results show that developmental-stage-dependent cooperation between RANK and CD40 promotes mTEC development, thereby establishing self-tolerance.
39128592
The cytokine RANKL produced by positively selected thymocytes fosters medullary thymic epithelial cells that express autoimmune regulator.
The thymic medulla provides a microenvironment where medullary thymic epithelial cells (mTECs) express autoimmune regulator and diverse tissue-restricted genes, contributing to launching self-tolerance. Positive selection is essential for thymic medulla formation via a previously unknown mechanism. Here we show that the cytokine RANK ligand (RANKL) was produced by positively selected thymocytes and regulated the cellularity of mTEC by interacting with RANK and osteoprotegerin. Forced expression of RANKL restored thymic medulla in mice lacking positive selection, whereas RANKL perturbation impaired medulla formation. These results indicate that RANKL produced by positively selected thymocytes is responsible for fostering thymic medulla formation, thereby establishing central tolerance.
19142351
Lymphotoxin Signal Promotes Thymic Organogenesis by Eliciting RANK Expression in the Embryonic Thymic Stroma
It has recently become clear that signals mediated by members of the TNFR superfamily, including lymphotoxin-β receptor (LTβR), receptor activator for NF-κB (RANK), and CD40, play essential roles in organizing the integrity of medullary thymic epithelial cells (mTECs) required for the establishment of self-tolerance. However, details of the mechanism responsible for the unique and cooperative action of individual and multiple TNFR superfamily members during mTEC differentiation still remain enigmatic. In this study, we show that the LTβR signal upregulates expression of RANK in the thymic stroma, thereby promoting accessibility to the RANK ligand necessary for mTEC differentiation. Cooperation between the LTβR and RANK signals for optimal mTEC differentiation was underscored by the exaggerated defect of thymic organogenesis observed in mice doubly deficient for these signals. In contrast, we observed little cooperation between the LTβR and CD40 signals. Thus, the LTβR signal exhibits a novel and unique function in promoting RANK activity for mTEC organization, indicating a link between thymic organogenesis mediated by multiple cytokine signals and the control of autoimmunity.
41688648
Osteoprotegerin and RANKL regulate bone resorption, density, geometry and strength.
Osteoprotegerin (OPG) and receptor activator of nuclear factor-kappaB ligand (RANKL) are dominant regulators of bone resorption. Many hormones, cytokines and growth factors mediate bone resorption by altering the ratio of RANKL to OPG. RANKL and OPG expression is also altered in numerous bone diseases, and these changes can reflect disease etiology or compensatory responses to disease. RANKL stimulates osteoclast formation, function and survival, and each of these effects is inhibited by OPG. OPG suppresses bone resorption and increases the density, area and strength of both cancellous and cortical bone. Denosumab (AMG 162), a fully human monoclonal antibody to RANKL, shares the pharmacologic attributes of OPG but has a significantly longer half-life that allows less frequent administration.
2259451
Stress and disorders of the stress system
All organisms must maintain a complex dynamic equilibrium, or homeostasis, which is constantly challenged by internal or external adverse forces termed stressors. Stress occurs when homeostasis is threatened or perceived to be so; homeostasis is re-established by various physiological and behavioral adaptive responses. Neuroendocrine hormones have major roles in the regulation of both basal homeostasis and responses to threats, and are involved in the pathogenesis of diseases characterized by dyshomeostasis or cacostasis. The stress response is mediated by the stress system, partly located in the central nervous system and partly in peripheral organs. The central, greatly interconnected effectors of this system include the hypothalamic hormones arginine vasopressin, corticotropin-releasing hormone and pro-opiomelanocortin-derived peptides, and the locus ceruleus and autonomic norepinephrine centers in the brainstem. Targets of these effectors include the executive and/or cognitive, reward and fear systems, the wake–sleep centers of the brain, the growth, reproductive and thyroid hormone axes, and the gastrointestinal, cardiorespiratory, metabolic, and immune systems. Optimal basal activity and responsiveness of the stress system is essential for a sense of well-being, successful performance of tasks, and appropriate social interactions. By contrast, excessive or inadequate basal activity and responsiveness of this system might impair development, growth and body composition, and lead to a host of behavioral and somatic pathological conditions.
11740311
Exposure to hypergravity during the preweaning but not postweaning period reduces vestibular-related stress responses in rats.
Gravitational forces, including hypergravity or microgravity, induce plasticity of vestibular-related functions. These functions are not easily reversed if exposure to the gravitational forces occurs during vestibular development. In the present study, we hypothesized that vestibular-related stress responses might be suppressed in rats exposed to hypergravity during the vestibular development period. We exposed the rats to 2 g (hypergravity) during the preweaning (BW-HG; embryonic day 14 to postnatal week 3) or postweaning (AW-HG; postnatal weeks 4-6) periods. After recovery for 4 wk at 1 g, we conducted rotarod tests and then exposed the rats to 2 g for 90 min. In BW-HG rats, vestibular-related motor coordination on the rotarod test was partially, but not fully, restored to the level of AW-HG rats or rats raised at 1 g (1-G group). Loading-induced plasma adrenocorticotropic hormone and corticosterone levels were significantly suppressed in BW-HG and in rats with a vestibular lesion compared with AW-HG and 1-G rats. Arginine vasopressin and Fos expression levels in the paraventricular hypothalamic nucleus were also significantly lower in BW-HG and vestibular lesion rats than in AW-HG and 1-G rats. By contrast, there was no difference in the electrical foot shock-induced increase in plasma corticosterone among the experimental groups, suggesting that the nonvestibular-related stress response was not suppressed by exposure to 2 g during preweaning. These results indicated that exposure to hypergravity during preweaning specifically suppressed the vestibular-related stress response, and this suppression did not recover after 4 wk at 1 g.
1774754
Vestibular-mediated increase in central serotonin plays an important role in hypergravity-induced hypophagia in rats.
Exposure to a hypergravity environment induces acute transient hypophagia, which is partially restored by a vestibular lesion (VL), suggesting that the vestibular system is involved in the afferent pathway of hypergravity-induced hypophagia. When rats were placed in a 3-G environment for 14 days, Fos-containing cells increased in the paraventricular hypothalamic nucleus, the central nucleus of the amygdala, the medial vestibular nucleus, the raphe nucleus, the nucleus of the solitary tract, and the area postrema. The increase in Fos expression was completely abolished or significantly suppressed by VL. Therefore, these regions may be critical for the initiation and integration of hypophagia. Because the vestibular nucleus contains serotonergic neurons and because serotonin (5-HT) is a key neurotransmitter in hypophagia, with possible involvement in motion sickness, we hypothesized that central 5-HT increases during hypergravity and induces hypophagia. To examine this proposition, the 5-HT concentrations in the cerebrospinal fluid were measured when rats were reared in a 3-G environment for 14 days. The 5-HT concentrations increased in the hypergravity environment, and these increases were completely abolished in rats with VL. Furthermore, a 5-HT(2A) antagonist (ketanserin) significantly reduced 3-G (120 min) load-induced Fos expression in the medial vestibular nucleus, and chronically administered ketanserin ameliorated hypergravity-induced hypophagia. These results indicate that hypergravity induces an increase in central 5-HT via the vestibular input and that this increase plays a significant role in hypergravity-induced hypophagia. The 5-HT(2A) receptor is involved in the signal transduction of hypergravity stress in the vestibular nucleus.
36850536
Leptin protects mice from starvation-induced lymphoid atrophy and increases thymic cellularity in ob/ob mice.
Thymic atrophy is a prominent feature of malnutrition. Forty-eight hours' starvation of normal mice reduced the total thymocyte count to 13% of that observed in freely fed controls, predominantly because of a diminution in the cortical CD4(+)CD8(+) thymocyte subpopulation. Prevention of the fasting-induced fall in the level of the adipocyte-derived hormone leptin by administering exogenous recombinant leptin protected mice from these starvation-induced thymic changes. The ob/ob mouse, which is unable to produce functional leptin because of a mutation in the obese gene, has impaired cellular immunity together with a marked reduction in the size and cellularity of the thymus. We found that ob/ob mice had a high level of thymocyte apoptosis resulting in a ratio of CD4(+)CD8(+) (cortical) to CD4(-)CD8(-) (precursor) thymocytes that was 4-fold lower than that observed in wild-type mice. Peripheral administration of recombinant leptin to ob/ob mice reduced thymocyte apoptosis and substantially increased both thymic cellularity and the CD4(+)CD8(+)/CD4(-)CD8(-) ratio. In contrast, a comparable weight loss in pair-fed PBS-treated ob/ob mice had no impact on thymocyte number. In vitro, leptin protected thymocytes from dexamethasone-induced apoptosis. These data indicate that reduced circulating leptin concentrations are pivotal in the pathogenesis of starvation-induced lymphoid atrophy.
35969161
Interleukin-22 Drives Endogenous Thymic Regeneration in Mice
IL-22 Protects the Thymus One of the side effects associated with radiation treatment and some types of chemotherapy is damage to the thymus. Immunological T cells develop in the thymus, and so damage to this organ results in immunodeficiency and increased susceptibility to infectious disease. Although the organ eventually recovers, therapies that speed this recovery process are of interest. Dudakov et al. (p. 91, published online 1 March; see the Perspective by Bhandoola and Artis) now show in mice that interleukin-22 (IL-22) production in the thymus is increased in response to radiation damage and that this cytokine promotes thymic repair. After radiation treatment, IL-23 production by thymic dendritic cells induced IL-22 secretion by a population of radio-resistant innate lymphoid cells. IL-22 appeared to mediate its effects by promoting the survival and proliferation of thymic epithelial cells. Damage to the thymus caused by infection or radiation is reversed by a cytokine. Endogenous thymic regeneration is a crucial function that allows for renewal of immune competence after stress, infection, or immunodepletion. However, the mechanisms governing this regeneration remain poorly understood. We detail such a mechanism, centered on interleukin-22 (IL-22) and triggered by the depletion of CD4+CD8+ double-positive thymocytes. Intrathymic levels of IL-22 were increased after thymic insult, and thymic recovery was impaired in IL-22–deficient mice. IL-22, which signaled through thymic epithelial cells and promoted their proliferation and survival, was up-regulated by radio-resistant RORγ(t)+CCR6+NKp46– lymphoid tissue inducer cells after thymic injury in an IL-23–dependent manner. Administration of IL-22 enhanced thymic recovery after total body irradiation. These studies reveal mechanisms of endogenous thymic repair and offer innovative regenerative strategies for improving immune competence.