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Disease exacerbation of multiple sclerosis is characterized by loss of terminally differentiated autoregulatory CD8 + T cells
Khrishen Cunnusamy, Ethan J. Baughman, Jorge Franco, Sterling B. Ortega, Sushmita Sinha, Parul Chaudhary, Benjamin M. Greenberg, Elliot M. Frohman, Nitin J. Karandikar
Clinical Immunology, Volume 152, Issues 1–2, May–June 2014, Pages 115–126
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.