*Purpose: Cardiac Allograft Vasculopathy (CAV) is a significant contributor to long term transplant rejection, despite advances in immunotherapy. Reactivity to alloantigen presentation may occur by either donor or recipient antigen presenting cells (APCs) to T-cells. A pathway that contributes to antigen presentation is the engulfment of apoptotic antigens by phagocytes. The TAM receptor tyrosine kinases (Tyro, AXL and MerTK) have been widely implicated in the regulation of apoptotic cell engulfment and the transduction of intracellular signaling that influences the innate inflammatory response. Dysfunction of TAMs is implicated in a variety of disease states including cancer, viral infection and autoimmune diseases; however, their influence on allograft transplant and subsequent CAV development is not well understood. We therefore hypothesized a role for TAMs during CAV.

*Methods: To address the role of AXL during experimental heart transplant, we utilized single and full MHC-II mismatch vascularized heart allograft models of CAV, making use of mice with targeted deletion of Axl. Long term graft survival was evaluated for rejection by routine palpitations and echocardiography. Flow cytometric and histological analyses were used to assess vasculopathy through immune cell infiltration, intimal thickness and extracellular matrix staining.

*Results: Our recent studies have shown that MerTK promotes allograft tolerance in an IFN-dependent manner. Here we demonstrate a contrasting role of AXL in both a single and full MHCII-mismatch cardiac allograft survival model. AXL promotes vasculopathy, as recipients deficient in Axl showed decreased intimal thickening and reduced vascular smooth muscle cell proliferation, resulting in prolonged graft survival compared to controls. Of particular importance, these results were recapitulated in recipients that had received bone marrow transplants from AXL deficient donors, indicating that AXL in the myeloid cell compartment contributes to CAV. Given these results we sought to investigate how AXL may affect antigen presentation and alter effector T-cell activation. In vitro leukocyte co-culture experiments revealed that AXL deficient dendritic cells (DCs) stimulated significantly less T-cell activation and proliferation compared to controls, and this was linked to decreased MHCII expression.

*Conclusions: Altogether our studies suggest a crucial role of myeloid derived AXL in the progression of CAV by modulating allo-recognition and effector T-cell activation. The availability of targeted AXL inhibitors could provide novel avenues for combinatorial treatments to prolong cardiac graft survival by diminishing DC/T-cell interactions.

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