Immune checkpoints in central nervous system autoimmunity.
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.
Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115-5817, USA.
Nicole
N
Joller
Anneli
A
Peters
Ana C
AC
Anderson
Vijay K
VK
Kuchroo
D000818:Animals; D020274:Autoimmune Diseases of the Nervous System / Q000235:genetics / Q000276:immunology; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology*; D060908:CTLA-4 Antigen / Q000235:genetics / Q000276:immunology; D002490:Central Nervous System / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D011971:Receptors, Immunologic / Q000235:genetics / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism
D060908:CTLA-4 Antigen; D011971:Receptors, Immunologic