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

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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References

  1. 1

    Mellman, I. & Steinman, R.M. Dendritic cells: specialized and regulated antigen processing machines. Cell 106, 255–258 (2001).

    CAS  Article  Google Scholar 

  2. 2

    Greenwald, R.J., Freeman, G.J. & Sharpe, A.H. The B7 family revisited. Annu. Rev. Immunol. 23, 515–548 (2005).

    Article  Google Scholar 

  3. 3

    Serra, P. et al. CD40 ligation releases immature dendritic cells from the control of regulatory CD4+CD25+ T cells. Immunity 19, 877–889 (2003).

    CAS  Article  Google Scholar 

  4. 4

    Seshasayee, D. et al. In vivo blockade of OX40 ligand inhibits thymic stromal lymphopoietin driven atopic inflammation. J. Clin. Invest. 117, 3868–3878 (2007).

    CAS  Article  Google Scholar 

  5. 5

    Coombes, J.L., Robinson, N.J., Maloy, K.J., Uhlig, H.H. & Powrie, F. Regulatory T cells and intestinal homeostasis. Immunol. Rev. 204, 184–194 (2005).

    CAS  Article  Google Scholar 

  6. 6

    Read, S., Malmstrom, V. & Powrie, F. Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25+CD4+ regulatory cells that control intestinal inflammation. J. Exp. Med. 192, 295–302 (2000).

    CAS  Article  Google Scholar 

  7. 7

    Sakaguchi, S., Sakaguchi, N., Asano, M., Itoh, M. & Toda, M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor α-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J. Immunol. 155, 1151–1164 (1995).

    CAS  PubMed  Google Scholar 

  8. 8

    Takahashi, T. et al. Immunologic self-tolerance maintained by CD25+CD4+ regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J. Exp. Med. 192, 303–310 (2000).

    CAS  Article  Google Scholar 

  9. 9

    McHugh, R.S. et al. CD4+CD25+ immunoregulatory T cells: gene expression analysis reveals a functional role for the glucocorticoid-induced TNF receptor. Immunity 16, 311–323 (2002).

    CAS  Article  Google Scholar 

  10. 10

    Bruder, D. et al. Neuropilin-1: a surface marker of regulatory T cells. Eur. J. Immunol. 34, 623–630 (2004).

    CAS  Article  Google Scholar 

  11. 11

    Hori, S., Nomura, T. & Sakaguchi, S. Control of regulatory T cell development by the transcription factor Foxp3. Science 299, 1057–1061 (2003).

    CAS  Article  Google Scholar 

  12. 12

    Yamazaki, S. et al. Effective expansion of alloantigen-specific Foxp3+CD25+CD4+ regulatory T cells by dendritic cells during the mixed leukocyte reaction. Proc. Natl. Acad. Sci. USA 103, 2758–2763 (2006).

    CAS  Article  Google Scholar 

  13. 13

    Ahn, J.S., Krishnadas, D.K. & Agrawal, B. Dendritic cells partially abrogate the regulatory activity of CD4+CD25+ T cells present in the human peripheral blood. Int. Immunol. 19, 227–237 (2007).

    CAS  Article  Google Scholar 

  14. 14

    Tarbell, K.V., Yamazaki, S., Olson, K., Toy, P. & Steinman, R.M. CD25+CD4+ T cells, expanded with dendritic cells presenting a single autoantigenic peptide, suppress autoimmune diabetes. J. Exp. Med. 199, 1467–1477 (2004).

    CAS  Article  Google Scholar 

  15. 15

    Lewkowich, I.P. et al. CD4+CD25+ T cells protect against experimentally induced asthma and alter pulmonary dendritic cell phenotype and function. J. Exp. Med. 202, 1549–1561 (2005).

    CAS  Article  Google Scholar 

  16. 16

    Shimizu, J., Yamazaki, S., Takahashi, T., Ishida, Y. & Sakaguchi, S. Stimulation of CD25+CD4+ regulatory T cells through GITR breaks immunological self-tolerance. Nat. Immunol. 3, 135–142 (2002).

    CAS  Article  Google Scholar 

  17. 17

    Abbas, A.R. et al. Immune response in silico (IRIS): immune-specific genes identified from a compendium of microarray expression data. Genes Immun. 6, 319–331 (2005).

    CAS  Article  Google Scholar 

  18. 18

    Sakisaka, T. & Takai, Y. Biology and pathology of nectins and nectin-like molecules. Curr. Opin. Cell Biol. 16, 513–521 (2004).

    CAS  Article  Google Scholar 

  19. 19

    Fuchs, A. & Colonna, M. The role of NK cell recognition of nectin and nectin-like proteins in tumor immunosurveillance. Semin. Cancer Biol. 16, 359–366 (2006).

    CAS  Article  Google Scholar 

  20. 20

    Burshtyn, D.N., Yang, W., Yi, T. & Long, E.O. A novel phosphotyrosine motif with a critical amino acid at position -2 for the SH2 domain-mediated activation of the tyrosine phosphatase SHP-1. J. Biol. Chem. 272, 13066–13072 (1997).

    CAS  Article  Google Scholar 

  21. 21

    Kashiwada, M., Giallourakis, C.C., Pan, P.Y. & Rothman, P.B. Immunoreceptor tyrosine-based inhibitory motif of the IL-4 receptor associates with SH2-containing phosphatases and regulates IL-4-induced proliferation. J. Immunol. 167, 6382–6387 (2001).

    CAS  Article  Google Scholar 

  22. 22

    Fontenot, J.D. et al. Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity 22, 329–341 (2005).

    CAS  Article  Google Scholar 

  23. 23

    Clark, H.F. et al. The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment. Genome Res. 13, 2265–2270 (2003).

    CAS  Article  Google Scholar 

  24. 24

    He, Y. et al. Complexes of poliovirus serotypes with their common cellular receptor, CD155. J. Virol. 77, 4827–4835 (2003).

    CAS  Article  Google Scholar 

  25. 25

    Satoh-Horikawa, K. et al. Nectin-3, a new member of immunoglobulin-like cell adhesion molecules that shows homophilic and heterophilic cell-cell adhesion activities. J. Biol. Chem. 275, 10291–10299 (2000).

    CAS  Article  Google Scholar 

  26. 26

    Bottino, C. et al. Identification of PVR (CD155) and Nectin-2 (CD112) as cell surface ligands for the human DNAM-1 (CD226) activating molecule. J. Exp. Med. 198, 557–567 (2003).

    CAS  Article  Google Scholar 

  27. 27

    Fuchs, A., Cella, M., Giurisato, E., Shaw, A.S. & Colonna, M. Cutting edge: CD96 (tactile) promotes NK cell-target cell adhesion by interacting with the poliovirus receptor (CD155). J. Immunol. 172, 3994–3998 (2004).

    CAS  Article  Google Scholar 

  28. 28

    Reymond, N. et al. DNAM-1 and PVR regulate monocyte migration through endothelial junctions. J. Exp. Med. 199, 1331–1341 (2004).

    CAS  Article  Google Scholar 

  29. 29

    Tahara-Hanaoka, S. et al. Functional characterization of DNAM-1 (CD226) interaction with its ligands PVR (CD155) and nectin-2 (PRR-2/CD112). Int. Immunol. 16, 533–538 (2004).

    CAS  Article  Google Scholar 

  30. 30

    Wiesmann, C. & de Vos, A.M. Nerve growth factor: structure and function. Cell. Mol. Life Sci. 58, 748–759 (2001).

    CAS  Article  Google Scholar 

  31. 31

    Dardalhon, V. et al. CD226 is specifically expressed on the surface of Th1 cells and regulates their expansion and effector functions. J. Immunol. 175, 1558–1565 (2005).

    CAS  Article  Google Scholar 

  32. 32

    Xia, C.Q. & Kao, K.J. Suppression of interleukin-12 production through endogenously secreted interleukin-10 in activated dendritic cells: involvement of activation of extracellular signal-regulated protein kinase. Scand. J. Immunol. 58, 23–32 (2003).

    CAS  Article  Google Scholar 

  33. 33

    Linsley, P.S. et al. Immunosuppression in vivo by a soluble form of the CTLA-4 T cell activation molecule. Science 257, 792–795 (1992).

    CAS  Article  Google Scholar 

  34. 34

    Wakkach, A. et al. Characterization of dendritic cells that induce tolerance and T regulatory 1 cell differentiation in vivo. Immunity 18, 605–617 (2003).

    CAS  Article  Google Scholar 

  35. 35

    Jiang, A. et al. Disruption of E-cadherin-mediated adhesion induces a functionally distinct pathway of dendritic cell maturation. Immunity 27, 610–624 (2007).

    Article  Google Scholar 

  36. 36

    van Kooyk, Y. & Geijtenbeek, T.B. DC-SIGN: escape mechanism for pathogens. Nat. Rev. Immunol. 3, 697–709 (2003).

    CAS  Article  Google Scholar 

  37. 37

    Chieppa, M. et al. Cross-linking of the mannose receptor on monocyte-derived dendritic cells activates an anti-inflammatory immunosuppressive program. J. Immunol. 171, 4552–4560 (2003).

    CAS  Article  Google Scholar 

  38. 38

    Steinman, R.M. et al. Dendritic cell function in vivo during the steady state: a role in peripheral tolerance. Ann. NY Acad. Sci. 987, 15–25 (2003).

    CAS  Article  Google Scholar 

  39. 39

    Agrawal, S. et al. Cutting edge: different Toll-like receptor agonists instruct dendritic cells to induce distinct Th responses via differential modulation of extracellular signal-regulated kinase-mitogen-activated protein kinase and c-Fos. J. Immunol. 171, 4984–4989 (2003).

    CAS  Article  Google Scholar 

  40. 40

    Fehervari, Z. & Sakaguchi, S. Development and function of CD25+CD4+ regulatory T cells. Curr. Opin. Immunol. 16, 203–208 (2004).

    CAS  Article  Google Scholar 

  41. 41

    Fallarino, F. et al. Modulation of tryptophan catabolism by regulatory T cells. Nat. Immunol. 4, 1206–1212 (2003).

    CAS  Article  Google Scholar 

  42. 42

    Ikeda, W. et al. Tage4/Nectin-like molecule-5 heterophilically trans-interacts with cell adhesion molecule Nectin-3 and enhances cell migration. J. Biol. Chem. 278, 28167–28172 (2003).

    CAS  Article  Google Scholar 

  43. 43

    Takai, Y., Miyoshi, J., Ikeda, W. & Ogita, H. Nectins and nectin-like molecules: roles in contact inhibition of cell movement and proliferation. Nat. Rev. Immunol. 9, 603–615 (2008).

    CAS  Article  Google Scholar 

  44. 44

    Gonzalez, L.C. et al. A coreceptor interaction between the CD28 and TNF receptor family members B and T lymphocyte attenuator and herpesvirus entry mediator. Proc. Natl. Acad. Sci. USA 102, 1116–1121 (2005).

    CAS  Article  Google Scholar 

  45. 45

    Shields, R.L. et al. High resolution mapping of the binding site on human IgG1 for FcγRI, FcγRII, FcγRIII, and FcRn and design of IgG1 variants with improved binding to the FcγR. J. Biol. Chem. 276, 6591–6604 (2001).

    CAS  Article  Google Scholar 

  46. 46

    Osheroff, P.L. et al. Receptor binding and biological activity of mammalian expressed sensory and motor neuron-derived factor (SMDF). Growth Factors 16, 241–253 (1999).

    CAS  Article  Google Scholar 

  47. 47

    Caparros, E. et al. DC-SIGN ligation on dendritic cells results in ERK and PI3K activation and modulates cytokine production. Blood 107, 3950–3958 (2006).

    CAS  Article  Google Scholar 

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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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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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