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

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.

Distinct roles for Blimp-1 in autoreactive CD4 T cells during priming and effector phase of autoimmune encephalomyelitis

“…The PD-1 is an important immune checkpoint role that negatively regulates T effector function and EAE development (Carter et al , 2007, Nuro-Gyina et al , 2016). Therefore we compared the expression of PD-1 and its ligand, PD-L1, in myelin-specific CD4 T effector cells from immunized CKO mice and WT littermates during priming phase and effector phase of EAE.…”

Interleukin-7 Unveils Pathogen-Specific T Cells by Enhancing Antigen-Recall Responses

“…Previous studies showed that IL-7 can support immune-cell reconstitution in lymphopenic conditions [ 22–25 ], restore sepsis-induced lymphocyte dysfunctions ([ 37 , 38 ]), enhance effector function of autoreactive T cells [ 8–13 ], and expand tumor-reactive T cells [ 29 , 30 ]. We then asked whether pathogen-reactive T cells also benefited from IL-7 exposure.…”

“…Accordingly, IL-7 is expressed in inflamed tissues of patients with (rheumatic) autoimmune diseases, where it can be produced by several cell types [ 43 ] (including macrophages, dendritic cells, and fibroblasts) and favor pathogenic Th1- and Th17-associated cytokine secretion. Furthermore, dysregulated IL-7 expression or activation of CD127 were found in patients with autoimmune conditions [ 8–13 ], suggesting that IL-7 supports the function of pathogenic effector cells in autoimmunity. In agreement with this, blocking the IL-7R in experimental animal models ameliorated autoimmune disease manifestations [ 44 ].…”

“…In humans, mutations negatively affecting the levels of CD127 have been correlated with severe immunodeficiency [ 7 ]. Conversely, increased serum levels of IL-7 and/or dysregulated activation of CD127 are reported in patients with autoimmune conditions, including multiple sclerosis [ 8 , 9 ], rheumatoid arthritis [ 10 ], type-I diabetes [ 11 ], inflammatory bowel disease [ 12 ], and psoriasis [ 13 ].…”

Cathepsin C modulates myelin oligodendrocyte glycoprotein‐induced experimental autoimmune encephalomyelitis

“…; Nuro‐Gyina et al . ). Neuroprotective microglia/macrophage cells are found more than damaging microglia/macrophage cells during the early phase in acute EAE but damaging microglia/macrophage cells become abundant during peak and recovery phase of EAE (Ahn et al .…”