Disease exacerbation of multiple sclerosis is characterized by loss of terminally differentiated autoregulatory CD8+ T cells

Abstract Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system (CNS). Although its etiology remains unknown, pathogenic T cells are thought to underlie MS immune pathology. We recently showed that MS patients harbor CNS-specific CD8 + Tregs that are deficien...

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Published in:Clinical immunology (Orlando, Fla.) Fla.), 2014-05, Vol.152 (1), p.115-126
Main Authors: Cunnusamy, Khrishen, Baughman, Ethan J, Franco, Jorge, Ortega, Sterling B, Sinha, Sushmita, Chaudhary, Parul, Greenberg, Benjamin M, Frohman, Elliot M, Karandikar, Nitin J
Format: Article
Language:English
Subjects:
Adult
Aged
Allergy and Immunology
CD8
CD8-Positive T-Lymphocytes - immunology
Cell Differentiation - immunology
Disease Progression
Female
Granzymes - biosynthesis
Granzymes - immunology
Histocompatibility Antigens Class I - immunology
Humans
IL-12
Interferon-gamma - immunology
Interleukin-12 - pharmacology
Interleukin-2 Receptor alpha Subunit - metabolism
Leukocyte Common Antigens - metabolism
Lymphocyte Activation - immunology
Male
Middle Aged
Multiple sclerosis
Multiple Sclerosis - immunology
Multiple Sclerosis - pathology
Perforin - immunology
Regulatory
T cells
T-Lymphocytes, Regulatory - immunology
Tumor Necrosis Factor Receptor Superfamily, Member 7 - metabolism
Up-Regulation
Young Adult
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Summary:Abstract Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system (CNS). Although its etiology remains unknown, pathogenic T cells are thought to underlie MS immune pathology. We recently showed that MS patients harbor CNS-specific CD8 + Tregs that are deficient during disease relapse. We now demonstrate that CNS-specific CD8 + Tregs were cytolytic and could eliminate pathogenic CD4 + T cells. These CD8 + Tregs were present primarily in terminally differentiated (CD27 −, CD45RO −) subset and their suppression was IFNγ, perforin and granzyme B-dependent. Interestingly, MS patients with acute relapse displayed a significant loss in terminally differentiated CD8 + T cells, with a concurrent loss in expression of perforin and granzyme B. Pre-treatment of exacerbation-derived CD8 + T cells with IL-12 significantly restored suppressive capability of these cells through upregulation of granzyme B. Our studies uncover immune-suppressive mechanisms of CNS-specific CD8 + Tregs, and may contribute to design of novel immune therapies for MS.
ISSN:1521-6616
1521-7035
DOI:10.1016/j.clim.2014.03.005