title: The TIGIT/CD226 axis regulates human T cell function.
abstract: T cell Ig and ITIM domain (TIGIT) is a newly identified receptor expressed on T cells that binds to CD155 on the dendritic cell surface, driving them to a more tolerogenic phenotype. Given that TIGIT contains an ITIM motif in its intracellular domain and considering the potential importance of the TIGIT/CD226 pathway in human autoimmune disease, we investigated the specific role of TIGIT in human CD4(+) T cells. Using an agonistic anti-TIGIT mAb, we demonstrate a direct inhibitory effect on T cell proliferation with a decrease in expression of T-bet, GATA3, IFN regulatory factor 4, and retinoic acid-related orphan receptor c with inhibition of cytokine production, predominantly IFN-γ. Knockdown of TIGIT expression by short hairpin RNA resulted in an increase of both T-bet and IFN-γ mRNA and protein expression with concomitant decrease in IL-10 expression. Increases in IFN-γ with TIGIT knockdown could be overcome by blocking CD226 signaling, indicating that TIGIT exerts immunosuppressive effects by competing with CD226 for the same CD155 ligand. These data demonstrate that TIGIT can inhibit T cell functions by competing with CD226 and can also directly inhibit T cells in a T cell-intrinsic manner. Our results provide evidence for a novel role of this alternative costimulatory pathway in regulating human T cell responses associated with autoimmune disease.
authors.affiliation: Department of Neurology, Yale School of Medicine, New Haven, CT 06520-8018, USA.
authors.forename: Ester
authors.initials: E
authors.lastname: Lozano
authors.forename: Margarita
authors.initials: M
authors.lastname: Dominguez-Villar
authors.forename: Vijay
authors.initials: V
authors.lastname: Kuchroo
authors.forename: David A
authors.initials: DA
authors.lastname: Hafler
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D002450:Cell Communication; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics / Q000276:immunology*; D034741:RNA, Small Interfering / Q000235:genetics; D011971:Receptors, Immunologic / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011991:Receptors, Virus / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction; D020825:T-Box Domain Proteins / Q000235:genetics / Q000276:immunology; D000098862:T Lineage-Specific Activation Antigen 1; D000098815:T-bet Transcription Factor
chemical_list: D000911:Antibodies, Monoclonal; D000945:Antigens, Differentiation, T-Lymphocyte; D000098862:T Lineage-Specific Activation Antigen 1; D016207:Cytokines; D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; D034741:RNA, Small Interfering; D011971:Receptors, Immunologic; D011991:Receptors, Virus; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; C534712:TIGIT protein, human; C066100:poliovirus receptor