TIGIT (also called T cell immunoreceptor with Ig and ITIM domains) is an immune receptor present on some T cells and Natural Killer Cells(NK). It is also identified as WUCAM and Vstm3. TIGIT could bind to CD155(PVR) on dendritic cells(DCs), macrophages, etc. with high affinity, and also to CD112(PVRL2) with lower affinity.
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. 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
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. 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. Blocking these pathways with novel targeted monoclonal antibodies synergistically rejuvenated HIV-specific CD8+ T cell responses. 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. This pathway can potentially be targeted to enhance killing of HIV infected cells during "Shock and Kill" HIV curative approaches.
TIGIT and PD-1 has been shown to be over expressed on tumor antigen-specific (TA-specific) CD8+ T cells and CD8+ tumor infiltrating lymphocytes (TILs) from individuals with melanoma . 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. It can be considered an immune checkpoint. Co-blockade of TIGIT and PD-1 pathways elicits tumor rejection in preclinical murine models.
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- Pharmaceutical Leaders Highlight Promise of TIGIT. Feb 2017
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