GITR induced transcriptional co-regulator PRDM16 selectively enhances T cell memory in the lung tissue following respiratory influenza infection 4025

Abstract Description GITR, a costimulatory TNFR superfamily member plays an important role in effector and memory CD8 T cell accumulation in the lung following influenza A virus infection (IAV). PRDM16 is a transcriptional coregulator known for its role in fatty acid metabolism and mitochondrial biogenesis in brown adipose tissue and hematopoietic stem cells. We previously identified Prdm16 as one of the most significantly upregulated genes induced by GITR signaling during chronic LCMV infection (Chang et al. Immunity 2017). Here we show that conditional knockout of Prdm16 in T cells results in a selective defect in effector and tissue resident memory CD8 T cells in the lung tissue with minimal effects in the secondary lymphoid organs and a trend towards increased Teffector responses in the lung during respiratory IAV infection. Conversely, overexpression of Prdm16 in OT-I T cells followed by adoptive transfer and IAV infection resulted in decreased effector T cell responses but increased memory T cell responses in the lung tissue compared to mock transduced OT-I T cells. Single cell RNA-sequencing of WT and Prdm16-/- CD8 T cells from mixed bone marrow chimeras following IAV infection suggests that PRDM16 induces a distinct state in the WT effector T cells that is not observed in the Prdm16-/- T cells. Our study identifies PRDM16 as an important regulator of memory T cells in the lung tissue with work in progress to identify mechanism. Funding Sources Funding: This research was supported by Canadian Institutes for health research grants #FDN-143250 and PJT-178020 (to T.H.W),an Ontario Graduate Scholarship (to KY) and Emerging & Pandemic Infections Consortium Doctoral Awards to S.L. and K.Y. T.H.W. holds the Canada research chair in anti-viral immunity at the University of Toronto. Topic Categories Viral Immunology (VIR)