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

•Neuroantigen-specific CD8 + T cells are terminally differentiated.•Neuroantigen-specific CD8 suppression is IFNγ, perforin and granzyme B-dependent.•Acute relapse in MS is associated with loss of terminally differentiated CD8 + T cells.•Suppressive potential of neuroantigen-specific CD8 cells can be restored with IL-12.

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.