Immune checkpoints in central nervous system autoimmunity

Summary: A number of autoimmune diseases, including multiple sclerosis, are mediated by self‐reactive T cells that have escaped the deletional mechanisms of central tolerance. Usually, these T cells are kept at bay through peripheral tolerance mechanisms, including regulation through coinhibitory receptors and suppression by regulatory T cells. However, if these mechanisms fail, self‐reactive T cells are activated and autoimmune responses ensue. This review outlines how the coinhibitory receptors CTLA‐4 (cytotoxic T‐lymphocyte antigen‐4), PD‐1 (programed death‐1), Tim‐3 (T‐cell immunoglobulin‐ and mucin domain‐containing molecule 3), and TIGIT (T‐cell immunoreceptor with immunoglobulin and ITIM domains) act at different checkpoints to inhibit autoreactive T cells and suppress the development of central nervous system autoimmunity. Loss of each of these receptors predisposes to autoimmunity, indicating a non‐redundant role in maintaining peripheral tolerance. At the same time, their functional patterns seem to overlap to a large degree. Therefore, we propose that only the concerted action of a combination of inhibitory receptors is able to maintain peripheral tolerance and prevent autoimmunity.