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 2764881. 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. doi:10.1371/journal.ppat.1005349. 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, and Hassane M. Zarour (April 2015). "TIGIT and PD-1 impair tumor antigen-specific CD8⁺ T cells in melanoma patients". J Clin Invest. 125(5) (1): 2046–2058. doi:10.1172/JCI80445. 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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