Abstract
BackgroundMultiple sclerosis (MS) is a chronic CNS autoimmune disease characterized by inflammation, demyelination, and neuronal degeneration, where myelin-specific CD4 T cells play critical roles in the formation of acute MS lesions and disease progression. The suppression of IL-7Rα expression and the upregulation of inhibitory receptors (PD-1, etc.) are essential parts of the cell-intrinsic immunosuppressive program regulating T effector functions to prevent autoimmunity. However, little is known on the factors regulating IL-7Rα/PD-1 balance in myelin-specific CD4 T effector/memory cells during the development of CNS autoimmunity.MethodsWe analyzed the roles of the transcription factor T-bet in regulating the expression of IL-7Rα and inhibitory receptors in myelin-specific CD4 T cells. Furthermore, we compared the effects of different inflammatory cytokines that are crucial for Th1 and Th17 development in regulating the IL-7Rα/PD-1 balance.ResultsWe discovered that T-bet suppresses the expression of inhibitory receptors (PD-1 and LAG-3) and promotes IL-7Rα expression in myelin-specific CD4 T cells in vitro and in vivo. As a result, T-bet skews IL-7Rα/PD-1 balance towards IL-7Rα and promotes enhanced effector function. Furthermore, IL-12 enhances IL-7Rα expression in a T-bet independent manner in myelin-specific Th1 cells. Meanwhile, IL-6, the cytokine inducing highly encephalitogenic Th17 differentiation, suppresses PD-1 while upregulating IL-7Rα, skewing IL-7Rα/PD-1 balance towards IL-7Rα, and promoting enhanced effector function. Moreover, blocking IL-7 signaling in myelin-specific CD4 T cells by αIL-7Rα significantly delays experimental autoimmune encephalomyelitis (EAE) onset and reduces disease severity.ConclusionsT-bet is a major transcription factor regulating IL-7Rα/PD-1 balance in myelin-specific CD4 T cells during EAE development, and there is a positive correlation between several major determinants promoting T cell encephalitogenicity (T-bet, IL-6, IL-12) and an IL-7Rα/PD-1 balance skewed towards IL-7Rα. Furthermore, IL-7 signaling inhibits PD-1 expression in myelin-specific CD4 T cells and blocking IL-7 signaling suppresses T cell encephalitogenicity. Therefore, interference with inhibitory pathways and IL-7Rα expression may suppress the encephalitogenic potential of myelin-specific CD4 T cells and have therapeutic benefits for MS patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0768-3) contains supplementary material, which is available to authorized users.
Highlights
Multiple sclerosis (MS) is a chronic central nervous system (CNS) autoimmune disease characterized by inflammation, demyelination, and neuronal degeneration, where myelin-specific CD4 T cells play critical roles in the formation of acute MS lesions and disease progression
The IL-7Rα expression on T effector/memory cells serves as an on-switch of T effector cell function, while the expression of the inhibitory receptor PD-1 serves as an off-switch to suppress the effector function of T cells, which plays an important role in the pathogenesis of autoimmune diabetes [14, 15]
Splenocytes from naïve Myelin basic protein (MBP)-specific TCR transgenic mice that were T-bet+/+ (TCR-WT) or T-bet−/− (TCR-T-bet−/−) were activated with MBP Ac1-11 for 72 h, followed by resting for 4 days, and reactivation with MBP Ac1-11 for 2 days
Summary
Multiple sclerosis (MS) is a chronic CNS autoimmune disease characterized by inflammation, demyelination, and neuronal degeneration, where myelin-specific CD4 T cells play critical roles in the formation of acute MS lesions and disease progression. The IL-7Rα expression on T effector/memory cells serves as an on-switch of T effector cell function, while the expression of the inhibitory receptor PD-1 serves as an off-switch to suppress the effector function of T cells, which plays an important role in the pathogenesis of autoimmune diabetes [14, 15] Both IL-7Rα [16,17,18,19,20,21] and the inhibitory receptor PD-1 [22,23,24] have been implicated in MS/EAE pathogenesis, it is not clear whether the key cytokines and/or transcription factors that are critical for T cell encephalitogenicity regulate IL-7Rα/PD-1 balance of myelin-specific CD4 T effector/memory cells during
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