TIGIT

TIGIT (also called T cell immunoreceptor with Ig and ITIM domains) is one newly discovered immune receptor on some percentage of T cells and Natural Killer Cells(NK).[1] It is also identified as WUCAM[2] and Vstm3.[3] TIGIT could bind to CD155(PVR) on dendritic cells(DCs), macrophages, etc. with high affinity, and also to CD112(PVRL2) with lower affinity.[1]

Research has shown that TIGIT-Fc fusion protein could interact with PVR on dendritic cells and increase its IL-10 secretion level/decrease its IL-12 secretion level under LPS stimulation, and also inhibit T cell activation in vivo.[1] TIGIT's inhibition of NK cytotoxicity can be blocked by antibodies against its interaction with PVR and the activity is directed through its ITIM domain[4]

Clinical Significance

During Human Immunodeficiency Virus (HIV) infection, TIGIT expressing CD8+ T cells has been shown to be expanded and associated with clinical markers of HIV disease progression in a diverse group of HIV infected individuals.[5] Elevated TIGIT levels remained sustained even among those with undetectable viral loads and a large fraction of HIV-specific CD8+ T cells simultaneously express both TIGIT and another negative checkpoint receptor, Programmed Death Protein 1 (PD-1) and retained several features of exhausted T cells.[5] Blocking these pathways with novel targeted monoclonal antibodies synergistically rejuvenated HIV-specific CD8+ T cell responses.[5] Further, the TIGIT pathway is active in the rhesus macaque non-human primate model, and mimics expression and function during Simian Immunodeficiency Virus (SIV) infection.[5] This pathway can potentially be targeted to enhance killing of HIV infected cells during "Shock and Kill" HIV curative approaches.[6]

TIGIT and PD-1 has been shown to be over expressed on tumor antigen-sepcific (TA-specific) CD8+ T cells and CD8+ tumor infiltrating lymphocytes (TILs) from individuals with melanoma .[7] Blockade of TIGIT and PD-1 led to increased cell proliferation, cytokine production, and degranulation of TA-specific CD8+ T cells and TIL CD8+ T cells.[7] Furthermore, co-blokcade of TIGIT and PD-1 pathways elicits tumor rejection in preclinical murine models.[8]

Blocking these pathways should be further explored to elicit potent anti-viral and anti-tumor CD8+ T cell effector functions to potential control or eliminate disease.

See also

References

  1. 1 2 3 Yu X, Harden K, Gonzalez LC, Francesco M, Chiang E, Irving B, Tom I, Ivelja S, Refino CJ, Clark H, Eaton D, Grogan JL (Jan 2009). "The surface protein TIGIT suppresses T cell activation by promoting the generation of mature immunoregulatory dendritic cells". Nat Immunol. 10 (1): 48–57. doi:10.1038/ni.1674. PMID 19011627.
  2. ↑ Boles KS, Vermi W, Facchetti F, Fuchs A, Wilson TJ, Diacovo TG, Cella M, Colonna M (Mar 2009). "A novel molecular interaction for the adhesion of follicular CD4 T cells to follicular DC". European Journal of Immunology. 39 (3): 695–703. doi:10.1002/eji.200839116.
  3. ↑ Levin SD, Taft DW, Brandt CS, and 21 others (Apr 2011). "Vstm3 is a member of the CD28 family and an important modulator of T-cell function". European Journal of Immunology. 41 (4): 902–15. doi:10.1002/eji.201041136.
  4. ↑ Stanietsky N, Simic H, Arapovic J, Toporik A, Levy O, Novik A, Levine Z, Beiman M, Dassa L, Achdout H, Stern-Ginossar N, Tsukerman P, Jonjic S, Mandelboim O (Oct 2009). "The interaction of TIGIT with PVR and PVRL2 inhibits human NK cell cytotoxicity". Proc Natl Acad Sci U S A. 106 (42): 17858–63. doi:10.1073/pnas.0903474106. PMC 2764881Freely accessible. PMID 19815499.
  5. 1 2 3 4 Chew GM, Fujita T, Webb GM, Burwitz BJ, Wu HL, Reed JS, et al. (Jan 2016). "TIGIT Marks Exhausted T Cells, Correlates with Disease Progression, and Serves as a Target for Immune Restoration in HIV and SIV Infection". PLoS Pathogens. 12: e1005349. doi:10.1371/journal.ppat.1005349. PMC 4704737Freely accessible. PMID 26741490.
  6. ↑ Steven G. Deeks (July 2012). "HIV: Shock and Kill". Nature. 487 (1): 439–440. doi:10.1038/487439a. PMID 22836995.
  7. 1 2 Joe-Marc Chauvin; Ornella Pagliano; Julien Fourcade; Zhaojun Sun; Hong Wang; Cindy Sander; John M. Kirkwood; Tseng-hui Timothy Chen; Mark Maurer; Alan J. Korman & Hassane M. Zarour (April 2015). "TIGIT and PD-1 impair tumor antigen-specific CD8⁺ T cells in melanoma patients". J Clin Invest. 125 (5): 2046–2058. doi:10.1172/JCI80445. PMC 4463210Freely accessible. PMID 25866972.
  8. ↑ Robert J. Johnston; Laetitia Comps-Agrar; Jason Hackney; Xin Yu; Mahrukh Huseni; Yagai Yang; Summer Park; Vincent Javinal; Henry Chiu; Bryan Irving; Dan L. Eaton; Jane L. Grogan (December 2014). "The Immunoreceptor TIGIT Regulates Antitumor and Antiviral CD8+ T Cell Effector Function". Cancer Cell. 26 (6): 923–937. doi:10.1016/j.ccell.2014.10.018. PMID 25465800.
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