Interleukin 17 (IL-17) is a cytokine associated with inflammation, autoimmunity and defense against some bacteria. Here we show that IL-17 can promote autoimmune disease through a mechanism distinct from its proinflammatory effects. As compared with wild-type mice, autoimmune BXD2 mice express more IL-17 and show spontaneous development of germinal centers (GCs) before they increase production of pathogenic autoantibodies. We show that blocking IL-17 signaling disrupts CD4 + T cell and B cell interactions required for the formation of GCs and that mice lacking the IL-17 receptor have reduced GC B cell development and humoral responses. Production of IL-17 correlates with upregulated expression of the genes Rgs13 and Rgs16, which encode regulators of G-protein signaling, and results in suppression of the B cell chemotactic response to the chemokine CXCL12. These findings suggest a mechanism by which IL-17 drives autoimmune responses by promoting the formation of spontaneous GCs.

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A major problem associated with adenovirus gene therapy is the T cell-mediated immune response, which is elicited by inoculation of the adenovirus vector and leads to rapid clearance of the virus and loss of transgene expression. In this study, the immune response to adenovirus was prevented by induction of specific T-cell tolerance by pretreatment with adenovirus-infected antigen-presenting cells (APC) that express Fas ligand. Compared with control-treated mice, the tolerized mice showed prolonged expression of lacZ upon administration of AdCMVlacZ 1 week after tolerance induction. In contrast to the control mice, the tolerized mice did not display proliferation of CD3+ T cells in the spleen in response to AdCMVlacZ. Tolerance induction also was indicated by the lower production of interferon-gamma and interleukin-2 by peripheral T cells isolated from AdCMVlacZ-challenged tolerized mice than by AdCMVlacZ-challenged control-treated mice. The T-cell tolerance was specific for the adenovirus as the T-cell responses to irrelative murine cytomegalovirus remained unimpaired. Our results indicate that adenovirus-specific T-cell tolerance can be induced by APCs that coexpress Fas ligand and adenovirus antigens. We propose that this new strategy can be used to induce tolerance to adenovirus vector gene therapy with resultant prolonged expression of the transgene.

SummaryThe Nur77/Nurrl family of DNA binding proteins has been reported to be required for the signal transduction of CD3/T cell receptor (TCR)-mediated apoptosis in T cell hybridomas. To determine the role of this family of DNA-binding proteins in thymic clonal deletion, transgenic (Tg) mice bearing a dominant negative mutation were produced. The transgene consisted of a truncated Nur77 (ANur77) gene encoding the DNA-binding domain of Nur77 ligated to a TCR-[3 enhancer resulting in early expression in thymocytes. Apoptosis of CD4+CD8 + thymocytes mediated by CD3/TCR signaling was greatly inhibited in the ANur77 Tg mice, compared with non-Tg littermates, after treatment with anti-CD3 or anti-TCR antibody in vivo and in vitro. Clonal deletion of self-reactive T cells was investigated in ANur77-Db/HY TCR-ot/~3 double Tg mice. There was a five-fold increase in the total number of thymocytes expressing self-reactive Db/HY TCR-et/~3 in the ANur77-TCR-ot/[3 double Tg male mice. Deficient clonal deletion of self-reactive thymocytes was demonstrated by a 10-fold increase in the CD4+CD8 + thymocytes that expressed Tg TCR-a/[~. There was an eight-fold increase in CD8 +, DB/Hy TCR-ot/[3 T cells in the lymph nodes (LN) of ANur77-Db/Hy TCR-o_/[3 double Tg compared with Db/Hy TCR-0~/I3 Tg male mice. In spite of defective clonal deletion, the T cells expressing the Tg TCR were functionally anergic. In vivo analysis revealed increased activation and apoptosis of T cells associated with increased expression of Fas and Fas ligand in LN of ANur77-Db/Hy TCR-oJI3 double Tg male mice. These results indicate that inhibition of Nur77/Nurrl DNA binding in T cells leads to inefficient thymic clonal deletion, but T cell tolerance is maintained by Fas-dependent clonal deletion in LN and spleen.

Germinal centers provide a microenvironment that promotes and regulates the interactions of B-cells with follicular T-helper cells (TFH). Here we show that there are significantly higher frequencies of CXCR5+ICOS+TFH cells in autoimmune BXD2 mice, and these cells express both interleukin (IL)-21R and IL-17RA. Although IL-17 and IL-21 are both important for the formation of spontaneous GCs and development of pathogenic autoantibodies, IL-21, but not IL-17, is required for the proper development of TFH cells in BXD2 mice. The total numbers of TFH cells and their ability to induce B cell responses in vitro were not affected by a deficiency of IL-17RA in BXD2-Il17ra−/− mice, the majority of CXCR5+ TFH cells from BXD2-Il17ra−/− mice were, however, not localized in the GC light zone (LZ). Interruption of IL-17 signaling, either acutely by AdIL-17R:Fc or chronically by Il17ra−/−, disrupted TFH–B interactions and abrogated the generation of autoantibody-forming B cells in BXD2 mice. IL-17 upregulated the expression of regulator of G-protein signaling (RGS)16 to promote the ability of TFH to form conjugates with B cells which was abolished in TFH cells from BXD2-Rgs16−/− mice. The results suggests that IL-17 is an extrinsic stop signal that it acts on post-differentiated IL-17RA+ TFH to enable its interaction with responder B cells in the LZ niche. These data suggest a novel concept that TFH differentiation and its stabilization in the LZ are two separate checkpoints and that IL-21 and IL-17 act at each checkpoint to enable pathogenic GC development.