? 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
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