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The surface protein TIGIT suppresses T cell activation by promoting the generation of mature immunoregulatory dendritic cells

Nature Immunology volume 10, pages 48–57 (2009)Cite this article

Abstract

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.

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Figure 1: Expression of TIGIT protein and mRNA in immune cells.
Figure 2: TIGIT binds to PVR family members.
Figure 3: Knockdown of TIGIT expression by TIGIT-specific siRNA.
Figure 4: Effect of TIGIT on T cells requires APCs.
Figure 5: Modification of DCs by TIGIT.
Figure 6: PVR signaling.
Figure 7: TIGIT-modified MDDCs inhibit T cell activation.
Figure 8: TIGIT-Fc decreases DTH in mice by a mechanism dependent on IL-10.

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Acknowledgements

We thank C. Adams and members of Antibody Engineering (Genentech) for generating anti-TIGIT; M. Balazs and Z. Lin for discussions and support with animal studies; and members of the FACS Lab (Genentech) for support in cell sorting.

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Author notes

  1. Xin Yu and Kristin Harden: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Immunology, Genentech, South San Francisco, 940804, California, USA

    Xin Yu, Michelle Francesco, Eugene Chiang, Bryan Irving, Sinisa Ivelja, Canio J Refino & Jane L Grogan

  2. Department of Protein Chemistry, Genentech, South San Francisco, 940804, California, USA

    Kristin Harden, Lino C Gonzalez, Irene Tom & Dan Eaton

  3. Department of Bioinformatics, Genentech, South San Francisco, 940804, California, USA

    Hilary Clark

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Contributions

X.Y. performed in vitroT cell and DC assays, FACS and siRNA experiments, Erk assays and mouse RNA analysis. K.H., L.C.G. and I.T. performed biosensor experiments. K.H. also performed FACS, radioligand binding experiments and PVR phosphorylation experiments. E.C., B.I., S.I. and C.J.R. helped conceptualize and perform DTH experiments. M.F. contributed to screening and characterization of mAbs. H.C. performed bioinformatics screens. J.L.G. and D.E. supervised the project and drafted the manuscript.

Corresponding author

Correspondence to Jane L Grogan.

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All authors work for Genetech, which develops and markets drugs for profit.

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Yu, X., Harden, K., C Gonzalez, L. et al. The surface protein TIGIT suppresses T cell activation by promoting the generation of mature immunoregulatory dendritic cells. Nat Immunol 10, 48–57 (2009). https://doi.org/10.1038/ni.1674

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