Cytotoxic T lymphocytes in multiple sclerosis: New targets for treatment?

Granzymes (Gzms) are proteases that are classically associated with triggering apoptosis in tumors or virus-infected cells. Despite their beneficial role in resolutive immune responses, there are evidences associating continuous Gzm release with sustained tissue damage in several conditions. At the same time, ectopic sources of Gzms, besides classical CD8+ T lymphocytes and NK cells, have been described in the literature. Thus, here, we have reviewed the mechanisms of cell death triggered by the five human Gzms—GzmA, GzmB, GzmH, GzmK, and GzmM—focusing especially on GzmB, the most powerful of these proteases in humans. Furthermore, we have summarized the involvement of ectopic “cytotoxic” CD4+ T lymphocytes (CD4-CTLs) in human diseases, mainly focusing on multiple sclerosis (MS), which has the largest descriptions of these subsets among all autoimmune diseases. In general, a better understanding of the physiopathological functions of Gzms may reveal promising targets for diagnostic/therapeutic approaches to treating diverse human diseases.