*Purpose: Belatacept resistant-rejection (BRR) is a major barrier to the widespread adoption of immune checkpoint blockade therapeutics in transplantation. Our lab has shown that patients experiencing BRR exhibit an increase in circulating Th17 cells compared to controls. Additionally, murine skin graft recipients containing Th17 skewed memory T cell compartments also exhibit CTLA4-Ig resistant rejection. Increased incidences of colitis, a Th17 mediated pathology, in cancer patients treated with CTLA-4 inhibitors reinforces the idea that Th17 cells are uniquely reliant on CTLA-4 signaling. As such, identifying pathways that control Th17 alloimmunity in the context of CD28/CTLA-4 blockade is a clinically important goal. Kuchroo and colleagues have shown that Th17 cells are regulated by TIGIT⁺ Tregs. Thus, we hypothesized that agonism of the TIGIT pathway might mitigate Th17-mediated costimulation blockade resistant rejection.

*Methods: To test this, we utilized a mouse model in which recipients were immunized to generate graft-specific Th17-polarized memory T cell compartment. Animals were then challenged with skin grafts and treated with either CTLA-4Ig alone or CTLA-4Ig + a TIGIT agonist.

*Results: Results indicated that addition of the TIGIT agonist led to a 1.4-fold decrease in the median frequency of IL-17-producing CD4+ T cells in the graft and draining lymph node compared to treatment with CTLA-4Ig alone. Interestingly, animals treated with the TIGIT agonist experienced a significant increase in the number of Foxp3+ CD4+ Tregs in the draining lymph node compared to animals treated with CTLA-4Ig alone (p= 0.0159 by two-tailed Mann-Whitney t-test). Taken together, these results suggest that the coinhibitory molecule TIGIT is a promising therapeutic target to overcome Th17-mediated costimulation blockade-resistant rejection in organ transplantation.

*Conclusions: Ongoing experiments are directed at employing a novel TIGIT fl/fl model to determine if the primary role of TIGIT agonism in prolonging graft survival is functioning at the level of Foxp3⁺ Treg (Foxp3-Cre x TIGIT^fl/fl) or is a cell-intrinsic effect on RORγt⁺ Th17 effectors (RORγt-CrexTIGIT^fl/fl). These models will allow us to understand the role of TIGIT in Th17-mediated costimulation blockade resistant rejection and propose therapeutic strategies for targeting TIGIT in Th17-mediated diseases.

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