Studies in infectious disease and autoimmunity models have shown that immune responses to both self and foreign antigens are frequently dominated by induction of a particular Th1/Th2 subset with profound consequences for clinical outcome. Although the inflammatory effector function of Th1 cells is essential for the clearance of intracellular pathogens, it is also responsible for the tissue damage typical of organ-specific autoimmunity. Th2 cells which play an important role in the clearance of many helminthic infections function as suppressor cells or ineffectual bystanders in organ-specific autoimmune diseases. We have focused our efforts on identification of the cytokines that play critical roles in the induction of Th1 and Th2 responses. Previous studies have suggested that activation of CD4+ T cells in the presence of IL-10 results in the generation of or a population of T cells, termed T regulatory 1 (Tr1) cells, that primarily produce IL-10 and TGF-beta, but not IL-4. The relationship between Tr1 cells and conventional Th2 cells remains unclear. We have not been successful in our attempts to generate significant numbers of antigen-specific t cells that secreted IL-10, but not IL-4, by performing cultures in the presence of IL-10 alone. The small numbers of cells that produced IL-10 only were completely dependent on the presence of IL-4 and signal transducer and activator of transcription 6 for their generation. Studies with myelin basic protein-specific T cells derived from an IL-4 deficient mouse confirmed the absolute requirement for the generation of IL-10 producers under all culture conditions. These IL-10 producing Th2 cells failed to inhibit experimental allergic encephalomyelitis (EAE) in an adoptive transfer model and were pathogenic when transferred to immunodeficient mice. These studies raise doubts about the existence of a unique population of CD4+ regulatory T cells that can be generated in the presence of IL-10. Myelin oligodendrocyte glycoprotein (MOG) represents an important target autoantigen in multiple sclerosis and in EAE in animals. We have generated a T cell receptor (TCR) transgenic (Tg) mouse expressing a TCR derived from an encephalotigenic T cell clone specific for MOG 35-55. This TCR Tg line failed to develop EAE spontaneously and only developed mild EAE at late onset even when immunized with MOG in adjuvant. The TCR Tg T cells produced large amounts of IL-4 when stimulated in vitro with MOG in the absence of exogenous IL-4 and underwent FAS/FAS-L mediated activation induced cell death when stimulated with MOG in the presence of IL-12. this phenotype was acquired in the periphery and not during T cell differentiation in the thymus and was not secondary to the presence of regulatory T cells. The unique phenotype of these autoantigen-specific T cells may represent an important mechanism of protection against autoimmune disease. TGF-beta, a pleiotropic cytokine that has multiple effects on immune responses, has been shown to inhibit IL-4/GATA-3 expression as well as Th2 differentiation. Consistent with these reports, we found that priming T cells from DO11.10 transgenic mice with antigen in the presence of TGF-beta inhibited GATA-3 expression and the development of IL-4-producing T cells. Unexpectedly, the inhibition of Th2 development was accompanied by a substantial increase in the number of IFN-gamma-producing cells. T cells primed with TGF-beta secreted IFN-gamma in response to both TCR ligation and IL-12/IL-18 stimulation, and expressed high levels of T-bet and low levels of GATA-3. The TGF-beta mediated enhancement of Th1 priming was independent of IL-12 and STAT-4, but required endogenous IFN-gamma. The TGF-beta-mediated enhancement of the IFN-gamma dependent, IL-12-independent pathway of Th1 priming was mediated primarily by the inhibition of the production of IL-4 by memory/activated T cells in the unfractionated CD4+ responder population. Nevertheless, TGF-beta did not inhibit this pathway of Th1 differentiation when naive CD4+ T cells were used as responders. These data have important implications for strategies being considered for the use of TGF-beta producing T cells for the treatment of autoimmune disorders.
NIH ExPorter
NIH ExPorter