title: Cutting edge: TIGIT has T cell-intrinsic inhibitory functions.
abstract: Costimulatory molecules regulate the functional outcome of T cell activation, and disturbance of the balance between activating and inhibitory signals results in increased susceptibility to infection or the induction of autoimmunity. Similar to the well-characterized CD28/CTLA-4 costimulatory pathway, a newly emerging pathway consisting of CD226 and T cell Ig and ITIM domain (TIGIT) has been associated with susceptibility to multiple autoimmune diseases. In this study, we examined the role of the putative coinhibitory molecule TIGIT and show that loss of TIGIT in mice results in hyperproliferative T cell responses and increased susceptibility to autoimmunity. TIGIT is thought to indirectly inhibit T cell responses by the induction of tolerogenic dendritic cells. By generating an agonistic anti-TIGIT Ab, we demonstrate that TIGIT can inhibit T cell responses directly independent of APCs. Microarray analysis of T cells stimulated with agonistic anti-TIGIT Ab revealed that TIGIT can act directly on T cells by attenuating TCR-driven activation signals.
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Joller
authors.forename: Jason P
authors.initials: JP
authors.lastname: Hafler
authors.forename: Boel
authors.initials: B
authors.lastname: Brynedal
authors.forename: Nasim
authors.initials: N
authors.lastname: Kassam
authors.forename: Silvia
authors.initials: S
authors.lastname: Spoerl
authors.forename: Steven D
authors.initials: SD
authors.lastname: Levin
authors.forename: Arlene H
authors.initials: AH
authors.lastname: Sharpe
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Kuchroo
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D015536:Down-Regulation / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology / Q000473:pathology; D020022:Genetic Predisposition to Disease; D006131:Growth Inhibitors / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology*; D007166:Immunosuppressive Agents / Q000378:metabolism / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D011971:Receptors, Immunologic / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism
chemical_list: D006131:Growth Inhibitors; D007166:Immunosuppressive Agents; D011971:Receptors, Immunologic; C556305:T cell Ig and ITIM domain protein, mouse