Regulation of effector function of CNS autoreactive CD4 T cells through inhibitory receptors and IL-7Rα

Background: 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 suppression of IL-7R alpha 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-7R alpha/PD-1 balance in myelin-specific CD4 T effector/memory cells during the development of CNS autoimmunity. Methods: We analyzed the roles of the transcription factor T-bet in regulating the expression of IL-7Ra 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-7R alpha/PD-1 balance. Results: We discovered that T-bet suppresses the expression of inhibitory receptors (PD-1 and LAG-3) and promotes IL-7R alpha expression in myelin-specific CD4 T cells in vitro and in vivo. As a result, T-bet skews IL-7R alpha/PD-1 balance towards IL-7R alpha and promotes enhanced effector function. Furthermore, IL-12 enhances IL-7Ra 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-7R alpha, skewing IL-7R alpha/PD-1 balance towards IL-7R alpha, and promoting enhanced effector function. Moreover, blocking IL-7 signaling in myelin-specific CD4 T cells by alpha IL-7R alpha significantly delays experimental autoimmune encephalomyelitis (EAE) onset and reduces disease severity. Conclusions: T-bet is a major transcription factor regulating IL-7R alpha/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-7R alpha/PD-1 balance skewed towards IL-7R alpha. 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-7R alpha expression may suppress the encephalitogenic potential of myelin-specific CD4 T cells and have therapeutic benefits for MS patients.