Targeting cDC1 with CAR T cells to investigate their role and potential as a therapeutic target in Type 1 diabetes

PROJECT SUMMARY Type 1 diabetes (T1D) is the second most common disease of childhood which results in substantial morbidity and mortality. This autoimmune disease is characterized by the infiltration of CD4 and CD8 T cells into the islets of Langerhans in the pancreas, where they ultimately deplete insulin-secreting  cells. Recent studies have shown that conventional type 1 dendritic cells (cDC1) are required for the development of Type 1 diabetes in the murine NOD model, which has many parallels to human disease. cDC1 are unique in their ability to efficiently cross-present  cell antigens to and prime autoreactive CD8 T cells. Furthermore, cDC1 are potent producers of IL-12 and may facilitate Th1 differentiation of CD4 T cells. A therapy that specifically eliminates cDC1 may therefore be expected to prevent the development of T1D by blocking autoreactive CD4 Th1 development as well as the presentation of self-antigens to autoreactive CD8 T cells. Our preliminary data show that a chimeric antigen receptor (CAR) T cell targeting XCR1, a chemokine receptor expressed by cDC1, is successful in depleting cDC1 in the spleen and pancreatic lymph node of NOD mice. Furthermore, cDC1 depletion by this CAR T cell also successfully inhibited the proliferation of a cDC1 dependent, self-reactive CD4 T cell in vivo. Thus, the central premise of this proposal is that XCL1 CAR T cells may be useful for the prevention of T1D. To address this, we will assess the ability of this CAR to prevent diabetes in NOD mice. Experiments proposed in Aim 1 will validate the specificity of the CAR for cDC1s and address the durability of cDC1 depletion in vivo. Aim 2 will assess the functional effects of cDC1 depletion by CAR T cells on autoimmune diabetes by assessing CD4 and CD8 T cell numbers and phenotypes within the islets as well as the rate of spontaneous diabetes incidence in NOD mice. Collectively, these studies may lead to the development of a novel preventative treatment for human Type 1 diabetes and establish a paradigm for CAR T cell mediated immunomodulation via selective targeting of DC subsets.