Autoregulatory CD8 T cells depend on cognate antigen recognition and CD4/CD8 myelin determinants

Ortega, Sterling B.; Kashi, Venkatesh P.; Cunnusamy, Khrishen; Franco, Jorge; Karandikar, Nitin J.

doi:10.1212/nxi.0000000000000170

Cited by 18 publications

(36 citation statements)

References 45 publications

(67 reference statements)

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“…This is in addition to work from our lab, which clearly demonstrated -in marked contrast to their CD4 + counterparts -neuroantigenspecific CD8 + T-cells failed to adoptively transfer EAE disease to naïve recipient mice (36). We have seen this protective CD8 + T-cells phenotype very robustly in several models of EAE (37).…”

Section: Regulatory Role For Cd8 + T-cells In Eaesupporting

confidence: 76%

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CD8+ T-Cells as Immune Regulators of Multiple Sclerosis

et al. 2015

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The vast majority of studies regarding the immune basis of MS (and its animal model, EAE) have largely focused on CD4+ T-cells as mediators and regulators of disease. Interestingly, CD8+ T-cells represent the predominant T-cell population in human MS lesions and are oligoclonally expanded at the site of pathology. However, their role in the autoimmune pathologic process has been both understudied and controversial. Several animal models and MS patient studies support a pathogenic role for CNS-specific CD8+ T-cells, whereas we and others have demonstrated a regulatory role for these cells in disease. In this review, we describe studies that have investigated the role of CD8+ T-cells in MS and EAE, presenting evidence for both pathogenic and regulatory functions. In our studies, we have shown that cytotoxic/suppressor CD8+ T-cells are CNS antigen-specific, MHC class I-restricted, IFNγ- and perforin-dependent, and are able to inhibit disease. The clinical relevance for CD8+ T-cell suppressive function is best described by a lack of their function during MS relapse, and importantly, restoration of their suppressive function during quiescence. Furthermore, CD8+ T-cells with immunosuppressive functions can be therapeutically induced in MS patients by glatiramer acetate (GA) treatment. Unlike CNS-specific CD8+ T-cells, these immunosuppressive GA-induced CD8+ T-cells appear to be HLA-E restricted. These studies have provided greater fundamental insight into the role of autoreactive as well as therapeutically induced CD8+ T-cells in disease amelioration. The clinical implications for these findings are immense and we propose that this natural process can be harnessed toward the development of an effective immunotherapeutic strategy.

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Section: Regulatory Role For Cd8 + T-cells In Eaesupporting

confidence: 76%

“…In our recently published and unpublished results, adoptive transfer of both MOG35-55-and PLP178-191-specific CD8 + T-cells can suppress EAE (34,65). Due to mechanistic studies, we will elaborate upon later that these cells are quite distinct from previously described Qa-1restricted CD8 + Tregs (37).…”

Section: Regulatory Role For Cd8 + T-cells In Eaementioning

confidence: 83%

CD8+ T-Cells as Immune Regulators of Multiple Sclerosis

et al. 2015

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“…In this regard, our myelin-specific Qa-1-restricted CD8 + Treg cells bear certain similarity to this recently reported neuroantigen-specific CD8 + Treg cell subset in terms of their shared specificity to myelin proteins and their dependency on IFN-γ and Perforin124449. However, the neuroantigen-specific CD8 + Treg cells differ from myelin-specific Qa-1-restricted CD8 + Treg cells in requiring classical MHC I molecules for presentation50. In addition, priming of the neuroantigen-specific CD8 + Treg cells requires the presence of both the regulatory and pathogenic epitopes in the same myelin protein50.…”

Section: Discussionsupporting

confidence: 82%

“…However, the neuroantigen-specific CD8 + Treg cells differ from myelin-specific Qa-1-restricted CD8 + Treg cells in requiring classical MHC I molecules for presentation50. In addition, priming of the neuroantigen-specific CD8 + Treg cells requires the presence of both the regulatory and pathogenic epitopes in the same myelin protein50. This second characteristic suggests that active immunization with such a regulatory neuroantigenic epitope is not a suitable therapy for MS.…”

Section: Discussionmentioning

confidence: 99%

Targeting Non-classical Myelin Epitopes to Treat Experimental Autoimmune Encephalomyelitis

Wang

Zhang

Baylink

et al. 2016

Sci Rep

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Qa-1 epitopes, the peptides that bind to non-classical major histocompatibility complex Ib Qa-1 molecules and are recognized by Qa-1-restricted CD8+ regulatory T (Treg) cells, have been identified in pathogenic autoimmune cells that attack myelin sheath in experimental autoimmune encephalomyelitis (EAE, an animal model for multiple sclerosis [MS]). Additionally, immunization with such epitopes ameliorates the EAE. However, identification of such epitopes requires knowledge of the pathogenic autoimmune cells which are largely unknown in MS patients. Hence, we asked whether the CD8+ Treg cells could directly target the myelin sheath to ameliorate EAE. To address this question, we analyzed Qa-1 epitopes in myelin oligodendrocyte glycoprotein (MOG that is a protein in myelin sheath). Here, we report identification of a MOG-specific Qa-1 epitope. Immunization with this epitope suppressed ongoing EAE, which was abrogated by CD8+ T cell depletion. Additionally, the epitope immunization activated the epitope-specific CD8+ T cells which specifically accumulated in the CNS-draining cervical lymph nodes. Finally, CD8+ T cells primed by the epitope immunization transferred EAE suppression. Hence, this study reveals a novel regulatory mechanism mediated by the CD8+ Treg cells. We propose that immunization with myelin-specific HLA-E epitopes (human homologues of Qa-1 epitopes) is a promising therapy for MS.

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“…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…”

Section: Discussionmentioning

confidence: 99%

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

Steinman

2016

Proc. Natl. Acad. Sci. U.S.A.

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Bile acids are ligands for the nuclear hormone receptor, farnesoid X receptor (FXR). The bile acid–FXR interaction regulates bile acid synthesis, transport, and cholesterol metabolism. Recently, bile acid–FXR regulation has been reported to play an integral role in both hepatic and intestinal inflammation, and in atherosclerosis. In this study, we found that FXR knockout mice had more disease severity in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Obeticholic acid (6α-ethyl-chenodeoxycholic acid, 6-ECDCA), a synthetic FXR agonist, is an orally available drug that is currently in clinical trials for the treatment of inflammatory diseases such as alcoholic hepatitis, nonalcoholic steatohepatitis, and primary biliary cirrhosis. When we treated mice exhibiting established EAE with 6-ECDCA, or the natural FXR ligand chenodeoxycholic acid (CDCA), clinical disease was ameliorated by (i) suppressing lymphocyte activation and proinflammatory cytokine production; (ii) reducing CD4+ T cells and CD19+ B cell populations and their expression of negative checkpoint regulators programmed cell death protein 1 (PD1), programmed death-ligand 1 (PD-L1), and B and T lymphocyte attenuator (BTLA); (iii) increasing CD8+ T cells and PD1, PDl-1, and BTLA expression; and (iv) reducing VLA-4 expression in both the T- and B-cell populations. Moreover, adoptive transfer of 6-ECDCA– or CDCA-treated donor cells failed to transfer disease in naive recipients. Thus, we show that FXR functions as a negative regulator in neuroinflammation and we highlight that FXR agonists represent a potential previously unidentified therapy for MS.

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Autoregulatory CD8 T cells depend on cognate antigen recognition and CD4/CD8 myelin determinants

Cited by 18 publications

References 45 publications

CD8+ T-Cells as Immune Regulators of Multiple Sclerosis

CD8+ T-Cells as Immune Regulators of Multiple Sclerosis

Targeting Non-classical Myelin Epitopes to Treat Experimental Autoimmune Encephalomyelitis

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

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