title: TIGIT predominantly regulates the immune response via regulatory T cells.
abstract: Coinhibitory receptors are critical for the maintenance of immune homeostasis. Upregulation of these receptors on effector T cells terminates T cell responses, while their expression on Tregs promotes their suppressor function. Understanding the function of coinhibitory receptors in effector T cells and Tregs is crucial, as therapies that target coinhibitory receptors are currently at the forefront of treatment strategies for cancer and other chronic diseases. T cell Ig and ITIM domain (TIGIT) is a recently identified coinhibitory receptor that is found on the surface of a variety of lymphoid cells, and its role in immune regulation is just beginning to be elucidated. We examined TIGIT-mediated immune regulation in different murine cancer models and determined that TIGIT marks the most dysfunctional subset of CD8+ T cells in tumor tissue as well as tumor-tissue Tregs with a highly active and suppressive phenotype. We demonstrated that TIGIT signaling in Tregs directs their phenotype and that TIGIT primarily suppresses antitumor immunity via Tregs and not CD8+ T cells. Moreover, TIGIT+ Tregs upregulated expression of the coinhibitory receptor TIM-3 in tumor tissue, and TIM-3 and TIGIT synergized to suppress antitumor immune responses. Our findings provide mechanistic insight into how TIGIT regulates immune responses in chronic disease settings.
authors.forename: Sema
authors.initials: S
authors.lastname: Kurtulus
authors.forename: Kaori
authors.initials: K
authors.lastname: Sakuishi
authors.forename: Shin-Foong
authors.initials: SF
authors.lastname: Ngiow
authors.forename: Nicole
authors.initials: N
authors.lastname: Joller
authors.forename: Dewar J
authors.initials: DJ
authors.lastname: Tan
authors.forename: Michele W L
authors.initials: MW
authors.lastname: Teng
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Kuchroo
authors.forename: Ana C
authors.initials: AC
authors.lastname: Anderson
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D003110:Colonic Neoplasms / Q000276:immunology / Q000473:pathology; D004268:DNA-Binding Proteins / Q000172:deficiency; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D000072597:Hepatitis A Virus Cellular Receptor 2; D016130:Immunophenotyping; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008546:Melanoma, Experimental / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D019707:Receptors, Chemokine / Q000096:biosynthesis / Q000235:genetics; D011971:Receptors, Immunologic / Q000172:deficiency / Q000502:physiology*; D011991:Receptors, Virus / Q000096:biosynthesis / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; C442241:Havcr2 protein, mouse; D000072597:Hepatitis A Virus Cellular Receptor 2; D009363:Neoplasm Proteins; C499308:Rag2 protein, mouse; D019707:Receptors, Chemokine; D011971:Receptors, Immunologic; D011991:Receptors, Virus; C556305:T cell Ig and ITIM domain protein, mouse; D014157:Transcription Factors