Regulatory cells, by virtue of their capacity to control the vigor of immune responses are essential to the maintenance of host homeostasis. Several types of CD4 regulatory T cells exist some of which are induced in response to infectious challenge and some of which are defined as natural regulators (natural Treg). Inducible Treg cells can develop from conventional CD4 T cells that are exposed to specific stimulatory conditions. Natural Treg cells, however, arise during the normal process of maturation in the thymus. Natural Treg play a central role in the control of autoimmunity, a function that is associated with their capacity to recognize self-antigen. Whether or not they also recognize foreign antigens and the extent of their repertoire for such antigens remain unknown. We and others have shown that natural Treg also play a critical role in the outcome of microbial infections. Natural Treg help limit collateral tissue damage caused by vigorous antimicrobial immune responses. These cells can also limit the magnitude of effector responses which result in failure to adequately control infection. Furthermore, there are clear evidences that the efficiency of vaccines can also be hampered by the presence of natural Treg. Thus, strategies aimed to manipulate natural Treg cells function or number, have clearly high therapeutic potential. Using three models of unicellular gastrointestinal parasitic infection (Cryptosporidium muris, Toxoplasma gondii and Encephalitozoon cuniculi) and one model of cutaneous infection (Leishmania major) we are exploring the antigen specificity of natural Treg that accumulate at sites of infections as well as the conditions that favor their retention, function and stability. Recent data, from our laboratory and others, clearly demonstrate that Treg accumulate at sites of infection. Although the mechanisms underlying this accumulation remain largely unknown, the influx of Treg is likely to depend on their antigen specificity as well as on appropriate host-derived signals for their recruitment and local survival. Differences in chemokine responsiveness or receptor expression between Treg and effector T cells have been demonstrated in various models. However, most of the available data were obtained using Treg purified from lymphoid organs in mice or peripheral blood in humans. There is virtually no data on the signals and molecules that are involved in the traffic and retention of Treg at local sites of infection where regulation takes place. Using animal model we are evaluated the mechanisms favoring the homing and retention of Treg at sites of infection in the skin or the gut. The targets of Treg control at sites of infection remain poorly understood. Intravital microscopy allows imaging of cells in live tissues and thus could shed light on Treg function. Previous intravital imaging of Treg has focused on dynamics of transferred transgenic cells within lymph nodes. Key findings include the lack of stable prolonged contact between Treg and effector T cells (Teff) as well as persistent contact between Treg and dendritic cells. In addition, previous work showed that Treg and effector T cells move in almost identical fashion in the pancreatic lymph node in a mouse model of diabetes. These findings call into question the importance of Treg-Teff contact in vivo and suggest a more important role for secreted cytokines or direct effects upon antigen presenting cells. Nevertheless, no studies have addressed the motility of Treg in tissue effector sites outside the lymph node. In addition, physiologic polyclonal T cell populations may behave differently from transferred transgenic cells. The aim of this project is to examine the behavior of polyclonal Treg in the dermis during parasitic Leishmania major infection. Characterizing their movement in the dermis will provide insight into mechanisms by which Treg are acting in tissues. Using a modelof lethal oral infection with Toxoplasma gondii, we examined the fate of both induced and natural Treg in the face of strong inflammatory responses occurring in a tolerogenic prone environment. We found that during highly Th1 polarized mucosal immune responses, Treg populations collapse via multiple pathways including blockade of Treg induction and disruption of endogenous Treg homeostasis. In particular, shutdown of IL 2 in the highly Th1 polarized environment triggered by infection directly contributes to Treg incapacity to parallel effector responses and eventually leads to immunopathogenesis. Furthermore, we found that environmental cues provided by both local dendritic cells and effector T cells can superimpose T bet and IFN &#947;expression by Treg. These data reveal a novel mechanism for Th1 pathogenicity that extends beyond their proinflammatory program to limit Treg survival.
NIH ExPorter
NIH ExPorter