TY - JOUR
T1 - Immune regulation of multiple sclerosis by CD8+ T cells
AU - Sinha, Sushmita
AU - Itani, Farah R.
AU - Karandikar, Nitin J.
N1 - Funding Information:
Acknowledgments This work was supported, in part, by Grant awards (to NJK) from the NIH and National MS Society. We thank
PY - 2014/8
Y1 - 2014/8
N2 - The role of CD8+ T cells in the process of autoimmune pathology has been both understudied and controversial. Multiple sclerosis (MS) is an inflammatory, demyelinating disorder of the central nervous system (CNS) with underlying T cell-mediated immunopathology. CD8+ T cells are the predominant T cells in human MS lesions, showing oligoclonal expansion at the site of pathology. It is still unclear whether these cells represent pathogenic immune responses or disease-regulating elements. Through studies in human MS and its animal model, experimental autoimmune encephalomyelitis (EAE), we have discovered two novel CD8+ T cell populations that play an essential immunoregulatory role in disease: (1) MHC class Ia-restricted neuroantigen-specific "autoregulatory" CD8+ T cells and (2) glatiramer acetate (GA/Copaxone®) therapy-induced Qa-1/HLA-E-restricted GA-specific CD8+ T cells. These CD8+ Tregs suppress proliferation of pathogenic CD4+ CD25- T cells when stimulated by their cognate antigens. Similarly, CD8+ Tregs significantly suppress EAE when transferred either pre-disease induction or during peak disease. The mechanism of disease inhibition depends, at least in part, on an antigen-specific, contact-dependent process and works through modulation of CD4+ T cell responses as well as antigen-presenting cells through a combination of cytotoxicity and cytokine-mediated modulation. This review provides an overview of our understanding of CD8+ T cells in immune-mediated disease, focusing particularly on our findings regarding regulatory CD8+ T cells both in MS and in EAE. Clinical relevance of these novel CD8-regulatory populations is discussed, providing insights into a potentially intriguing, novel therapeutic strategy for these diseases.
AB - The role of CD8+ T cells in the process of autoimmune pathology has been both understudied and controversial. Multiple sclerosis (MS) is an inflammatory, demyelinating disorder of the central nervous system (CNS) with underlying T cell-mediated immunopathology. CD8+ T cells are the predominant T cells in human MS lesions, showing oligoclonal expansion at the site of pathology. It is still unclear whether these cells represent pathogenic immune responses or disease-regulating elements. Through studies in human MS and its animal model, experimental autoimmune encephalomyelitis (EAE), we have discovered two novel CD8+ T cell populations that play an essential immunoregulatory role in disease: (1) MHC class Ia-restricted neuroantigen-specific "autoregulatory" CD8+ T cells and (2) glatiramer acetate (GA/Copaxone®) therapy-induced Qa-1/HLA-E-restricted GA-specific CD8+ T cells. These CD8+ Tregs suppress proliferation of pathogenic CD4+ CD25- T cells when stimulated by their cognate antigens. Similarly, CD8+ Tregs significantly suppress EAE when transferred either pre-disease induction or during peak disease. The mechanism of disease inhibition depends, at least in part, on an antigen-specific, contact-dependent process and works through modulation of CD4+ T cell responses as well as antigen-presenting cells through a combination of cytotoxicity and cytokine-mediated modulation. This review provides an overview of our understanding of CD8+ T cells in immune-mediated disease, focusing particularly on our findings regarding regulatory CD8+ T cells both in MS and in EAE. Clinical relevance of these novel CD8-regulatory populations is discussed, providing insights into a potentially intriguing, novel therapeutic strategy for these diseases.
KW - Experimental autoimmune encephalomyelitis (EAE)
KW - Glatiramer acetate (GA)
KW - Immunoregulatory
KW - Multiple sclerosis (MS)
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U2 - 10.1007/s12026-014-8529-9
DO - 10.1007/s12026-014-8529-9
M3 - Review article
C2 - 24845461
AN - SCOPUS:84905735685
SN - 0257-277X
VL - 59
SP - 254
EP - 265
JO - Immunologic Research
JF - Immunologic Research
IS - 1-3
ER -