Immune regulatory CNS-reactive CD8+T cells in experimental autoimmune encephalomyelitis

Abstract

Immune-based self-recognition and failure to modulate this response are believed to contribute to the debilitating autoimmune pathology observed in multiple sclerosis (MS). Studies from its murine model, experimental autoimmune encephalomyelitis (EAE), have shown that neuroantigen-specific CD4+ T cells are capable of inducing disease, while their immune sibling, the CD8+ T cells, have largely been ignored. To understand their role in autoimmune demyelination, we first confirmed that, similar to our observations in human MS, there is robust induction of neuroantigen-reactive CD8+ T cells in several models, including MOG 35-55 /CFA-induced EAE. However, MOG 35-55 -specific CD8+ T-cells, when purified, were unable to adoptively transfer disease into naïve mice (in contrast to CD4+ T-cells). In fact, we observed that the transfer of these neuroantigen-specific CD8+ T cells was able to suppress the induction of EAE and to inhibit ongoing EAE. These regulatory CD8+ T cells produced IFN-γ and perforin and were able to kill MOG loaded CD4+ T-cells as well as CD4-depleted APC, suggesting a cytotoxic/suppressor mechanism. Inhibition of EAE was associated with both the modulation of APC function as well as decreased MOG-specific CD4+ T cell responses. Our studies reveal a novel and unexpected immune regulatory function for neuroantigen-specific CD8+ T cells and have interesting biologic and therapeutic implications.

Obeticholic acid, a synthetic bile acid agonist of the farnesoid X receptor, attenuates experimental autoimmune encephalomyelitis

“…Myelin-specific CD8 + T cells have been shown to play a pathogenic role in EAE (38,39). However, more recently, myelin-specific autoregulatory CD8 + T cells have been shown to inhibit EAE, through the suppression of CD4 + T-cell and/or antigen-presenting cell function by direct killing in an antigenspecific manner (40,41). The fact that both FXR agonists increased the CD8 + T-cell population in vivo concurrently with increased PD1, PD-L1, and BTLA expression, suggests that a subset of autoregulatory CD8…”

CD8+ Tregs in autoimmunity: learning “self”-control from experience

“…Treg subset as well as certain CD8 ? Treg subsets express the IL-2 receptor alpha chain (CD25) [87,[89][90][91]93] and, in some instances, the beta chain (CD122) [32,40,49,53,103,111]. CD44 expression is also upregulated on Tregs [32,61,94,[112][113][114], and its level directly correlates with enhanced CD4 ?…”

“…And fourth, in at least some autoimmune disease states, disease-specific Tregs seem to expand and accumulate in situ upon disease onset [86,111,[126][127][128][129]. In a study by Godebu et al [123], in vitro-generated Tregs demonstrated self-antigen-driven propagation similar to that of memorylike Tregs when injected into NOD mice, in which a constant pressure exerted by the diabetes-associated autoantigens resulted in the selective expansion of certain clonotypes of Tregs with a skewing of Vb TCR usage.…”

Infectious Agents and Xenobiotics in the Etiology of Primary Biliary Cirrhosis

“…The development of such a model will allow us to overcome the major obstacles to the study of environmental determinants of PBC i.e. the long latency period prior to disease appearance and possibly control additional confounding factors [151] while identifying new therapeutic agents [152][153][154]. …”