The surface protein TIGIT suppresses T cell activation by promoting the generation of mature immunoregulatory dendritic cells.
Here we have identified a surface protein, TIGIT, containing an immunoglobulin variable domain, a transmembrane domain and an immunoreceptor tyrosine-based inhibitory motif that was expressed on regulatory, memory and activated T cells. Poliovirus receptor, which is expressed on dendritic cells, bound TIGIT with high affinity. A TIGIT-Fc fusion protein inhibited T cell activation in vitro, and this was dependent on the presence of dendritic cells. The binding of poliovirus receptor to TIGIT on human dendritic cells enhanced the production of interleukin 10 and diminished the production of interleukin 12p40. Knockdown of TIGIT with small interfering RNA in human memory T cells did not affect T cell responses. TIGIT-Fc inhibited delayed-type hypersensitivity reactions in wild-type but not interleukin 10-deficient mice. Our data suggest that TIGIT exerts immunosuppressive effects by binding to poliovirus receptor and modulating cytokine production by dendritic cells.
Yu
Xin
X
Department of Immunology, Genentech, South San Francisco, California 940804, USA.
Harden
Kristin
K
Gonzalez
Lino C
LC
Francesco
Michelle
M
Chiang
Eugene
E
Irving
Bryan
B
Tom
Irene
I
Ivelja
Sinisa
S
Refino
Canio J
CJ
Clark
Hilary
H
Eaton
Dan
D
Grogan
Jane L
JL
D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D002450:Cell Communication; D002454:Cell Differentiation; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D015536:Down-Regulation; D006801:Humans; D007108:Immune Tolerance; D007156:Immunologic Memory; D016753:Interleukin-10 / Q000096:biosynthesis; D053762:Interleukin-12 Subunit p40 / Q000378:metabolism; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D011485:Protein Binding; D011971:Receptors, Immunologic / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011991:Receptors, Virus / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
D053762:Interleukin-12 Subunit p40; D008565:Membrane Proteins; D011971:Receptors, Immunologic; D011991:Receptors, Virus; C534712:TIGIT protein, human; C066100:poliovirus receptor; D016753:Interleukin-10