1. Regulation of effector function of CNS autoreactive CD4 T cells through inhibitory receptors and IL-7Rα.
- Author
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Nuro-Gyina PK, Rieser EL, Granitto MC, Pei W, Liu Y, Lee PW, Aqel S, Zhang J, Lovett-Racke AE, Racke MK, and Yang Y
- Subjects
- Animals, Central Nervous System immunology, Cytokines metabolism, Disease Models, Animal, Gene Expression Regulation genetics, Mice, Mice, Transgenic, Myelin-Oligodendrocyte Glycoprotein immunology, Myelin-Oligodendrocyte Glycoprotein toxicity, Nerve Tissue Proteins deficiency, Nerve Tissue Proteins genetics, Peptide Fragments immunology, Peptide Fragments toxicity, Programmed Cell Death 1 Receptor metabolism, Receptors, Cell Surface deficiency, Receptors, Cell Surface genetics, Th1 Cells metabolism, CD4-Positive T-Lymphocytes metabolism, Central Nervous System pathology, Encephalomyelitis, Autoimmune, Experimental pathology, Encephalomyelitis, Autoimmune, Experimental surgery, Gene Expression Regulation immunology, Receptors, Interleukin-17 metabolism
- Abstract
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-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., Methods: We 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., Results: We 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., Conclusions: T-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.
- Published
- 2016
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