? PROJECT 1 The CD226/TIGIT pathway is a novel co-stimulatory/co-inhibitory pathway that closely parallels the CD28/CTLA-4 pathway. Similar to CD28 and CTLA-4, CD226 and TIGIT share ligands (CD112 and CD155) and ligand engagement of CD226 co-stimulates T cell activation while engagement of TIGIT inhibits T cell responses. Over the last few years, TIGIT has emerged as an important co-inhibitory receptor. While initial experiments indicated that TIGIT inhibits T cell responses indirectly by promoting tolerogenic phenotype in dendritic cells, we, and others, have shown that TIGIT has T cell-intrinsic inhibitory functions. We have now found that TIGIT is co-expressed with other co-inhibitory receptors (PD-1,Tim-3,Lag-3) on CD8+ T cells that exhibit dysfunctional/exhausted phenotype in chronic diseases such as cancer and chronic viral infection. Importantly, we find that expression of TIGIT marks the most dysfunctional subset of CD8+ T cells in these conditions, thus raising the important issue of how TIGIT co-operates with other inhibitory receptors to drive severe dysfunctional phenotype in effector T cells. In addition to its role in effector T cells, we have recently identified that TIGIT marks a distinct subset of regulatory T cells (Treg) that exhibit heightened expression of known Treg effector molecules and increased suppressive capacity. Importantly, we find that TIGIT+ Treg are highly enriched in inflamed tissues and that they exhibit specialized function; selectively suppressing pro- inflammatory Th1/Th17 responses while sparing Th2 responses. However, how TIGIT may function in CD8+ T cells to dampen their responses while in Treg function to direct specialized Treg function is not known. Given the data supporting important roles for TIGIT in regulating effector T cells and Treg, it is surprising that nothing is known regarding the molecular signals that induce TIGIT expression. Our preliminary data indicate that the immunomodulatory cytokine IL-27 induces TIGIT expression both in vitro and in vivo. We have now leveraged this information to identify candidate transcription factors that are downstream of IL-27 and may drive TIGIT expression in effector T cells. Based on our data, we hypothesize that TIGIT has a dual role in regulating T cell responses: 1) TIGIT co- operates with other co-inhibitory molecules to regulate effector T cell phenotype and 2) TIGIT drives highly active and specialized Treg phenotype in tissue. We have generated a number of tools including agonist and antagonist antibodies and conditional knock-out mice to study the function of this emerging pathway in the regulation of T cell responses.
Our specific aims are: 1) Dissect the T cell intrinsic and extrinsic roles of TIGIT in regulating T cell activation and dysfunction 2) Determine the role of TIGIT in directing Treg function in inflammatory conditions

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program Projects (P01)
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Special Emphasis Panel (ZAI1)
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Yale University
New Haven
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