Elucidating the molecular mechanisms involved in pleotropic cytokine signaling can lead to novel treatment approaches for autoimmune diseases that target proinflammatory functions while maintaining immune-regulatory functions. To that end, we sought to further investigate the immune-regulatory roles of the pleotropic cytokine IFN-γ. Previous studies demonstrated that IFN-γ prevents the differentiation of pathogenic Th17 cells. In addition, nitric oxide generated via inducible nitric oxide synthase (iNOS) prevents differentiation of Th17 cells by nitration of ROR-γT. However, it remains unresolved whether IFN-γ prevents Th17 differentiation directly via inducing nitric oxide (NO) and nitration of ROR-γT. In line with previous observations, we found an increase in the frequency of autoreactive Th17 cells and a decrease in iNOS expression and NO in the absence of IFN-γ in mice with experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. Additionally, the increase in Th17 cells in the absence of IFN-γ was reversible both in vitro and in vivo with treatment with a NO donor. This indicates a role for IFN-γ in inhibiting the differentiation of Th17 cells via iNOS-derived NO. We are currently elucidating the underlying mechanisms of NO mediated suppression and the molecular link between ROR-γt-nitration and decreased Th17 differentiation by flow cytometry, single-cell western blotting of key transcription factors, and in vivo adoptive transfer studies. Our studies may lead to a better understanding of the role of IFN-g and NO/iNOS axis in Th17 cell differentiation and autoimmune diseases.
Multiple sclerosis (MS) is a T cell-driven autoimmune disease. There are many unknowns regarding the disease etiology and pathogenesis. Importantly, the mechanisms of peripheral tolerance and dysregulation of pathogenic mechanisms are poorly understood. It is known that patients with MS exhibit myelin reactive T cells in the blood; however healthy controls also show myelin reactive T cells in the blood. Additionally, T cells from patients with MS react to many different myelin peptides. Current human studies do not support that patients exhibit large populations of T cells specific for a single myelin-antigen responsible for the induction of autoimmune pathology. In contrast, a quorum of several low avidity autoreactive T cells specific for one epitope might suffice to induce autoimmunity. We hypothesized that a quorum could be established and induce autoimmunity by small numbers of antigen-specific T cells recognizing different myelin antigen peptides. We found that disease in the experimental autoimmune encephalomyelitis (EAE) model of MS can be initiated by the cooperation of small numbers of myelin peptide-specific T cells reactive against different myelin epitopes. These results support the hypothesis that a quorum of autoreactive T cells could suffice to initiate autoimmune disease. We have developed a system whereby T cells of different antigen specificities can be traced in order to track the dynamics and kinetics of those T cells in disease initiation and progression. The results of this study provide further insights into the dynamic interactions between T cells of different antigen specificities.
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