Factors controlling effector T cell responses during central nervous system autoimmunity
Arbelaez, Carlos Antonio
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IL-17-producing CD4+ T (Th17) cells, along with IFN-gamma-expressing Th1 cells, represent two major pathogenic T cell subsets in experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS). The cytokines and transcription factors involved in the development and effector functions of Th1 and Th17 cells have been largely characterized. Among them, IL-23 is essential for the generation of stable and encephalitogenic Th17 cells and for the development of EAE. The IL-7/IL-7R signaling axis participates in cell survival, and perturbation of this pathway has been associated with enhanced susceptibility to MS. A link between IL-23-driven pathogenic T cells and IL-7/IL-7R signaling has previously been proposed but has not been formally addressed. Here, we showed that Th17 cells from mice with EAE express high levels of IL-7Ralpha compared to Th1 cells. Using mice that constitutively express IL-7Ralpha on T cells, we determined that sustained IL-7R expression in IL-23R deficient mice could not drive pathogenic T cells and the development of EAE. IL-7 inhibited the differentiation of Th17 cells but promoted IFN-gamma and GM-CSF secretion in vitro. In vivo IL-7/anti-IL-7 mAb complexes selectively expanded and enhanced the proliferation of CXCR3-expressing Th1 cells but did not impact Th17 cells and EAE development in wild-type and IL-23R-deficient mice. Importantly, high IL-7 expression was detected in the CNS during EAE and could drive the plasticity of Th17 cells to IFN-gamma-producing T cells. Together, these data address the contribution of IL-23/IL-23R and IL-7/IL-7R signaling in Th17 and Th1 cell dynamics during CNS autoimmunity. Moreover, we asked how the transcription factor STAT1 regulates the development of EAE. It is well established that the transcription factor STAT1 and its upstream cytokines, interferons and IL-27, serve a protective role in MS and EAE. Although STAT1 is critical in the stabilization of IFN-γ-producing CD4+ T helper (Th1) cells, which, together with IL-17-Th17 cells, drive the initiation of EAE, STAT1-deficient mice are highly susceptible to EAE. However, the mechanisms driving this effect remain elusive, particularly the role of STAT1 in CD4+ T cell responses. Here, we found that by using STAT1fl/fl/CD4-Cre mice, STAT1-deficient Th17 cells could not induce EAE, despite the fact that these cells produced higher levels of IL-17. Moreover, STAT1 deficiency in T cells rendered mice protected from EAE development. We found that STAT1 did not impact the proliferation or survival of CD4+ T cells activated in vitro, but in vivo activated STAT1-deficient T cells failed to proliferate and expand. We uncovered a novel role for STAT1 in driving the upregulation of MHC class I molecules on CD4+ T cells upon activation, thus making them susceptible to NK cell targeting. After depletion of NK cells, we observed improved and restored survival and expansion of STAT1-deficient CD4+ T cells, fully capable of inducing EAE. Our findings provide a novel role of STAT1 in protecting CD4+ T cells from NK cell-mediated cytotoxicity, furthering our understanding of the effect of interferon in the pathogenesis of MS.
- Immunology