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T-Cell Costimulatory Pathways and Their Influence in Inflammatory Disease

Costimulatory molecules can promote or inhibit T cell receptor mediated activation, playing an important role in fine-tuning TCR-mediated T cell activation. T cell function is ultimately dictated by an array of costimulatory signals, and it has become clear that the relative importance of a costimulatory pathway may vary depending on the T cell subset and the specific mechanism of pathogenesis.

Given that the alternative costimulatory pathway comprised of CD226 and its ligand CD155 has been associated with autoimmune diseases, including multiple sclerosis (MS) and type 1 diabetes (T1D), we investigated the functional role of CD226 and the effects of specifically targeting CD226 on human T cell responses. Furthermore, CD155 binds with higher affinity to TIGIT, a co-inhibitory receptor that can transduce a negative signal into activated T cells that attenuates T cell proliferation and cytokine production. In fact, ligation of TIGIT by agonistic antibody inhibits IL-2 production and T cell activation. In summary, targeting this costimulatory pathway may provide a therapeutic approach that specifically modulates the pro-inflammatory (Th1/Th17)/ anti-inflammatory (Th2) balance in a wide range of inflammatory diseases.