Lack Of Sprouty 1 And 2 Enhances Survival Of Effector Cd8(+) T Cells And Yields More Protective Memory Cells
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA(2018)
摘要
Identifying novel pathways that promote robust function and longevity of cytotoxic T cells has promising potential for immunotherapeutic strategies to combat cancer and chronic infections. We show that sprouty 1 and 2 (Spry1/2) molecules regulate the survival and function of memory CD8(+) T cells. Spry1/2 double-knockout (DKO) ovalbumin (OVA)-specific CD8(+) T cells (OT-I cells) mounted more vigorous autoimmune diabetes than WT OT-I cells when transferred to mice expressing OVA in their pancreatic beta-islets. To determine the consequence of Spry1/2 deletion on effector and memory CD8(+) T cell development and function, we used systemic infection with lymphocytic choriomeningitis virus (LCMV) Armstrong. Spry1/2 DKO LCMV gp33-specific P14 CD8(+) T cells survive contraction better than WT cells and generate significantly more polyfunctional memory T cells. The larger number of Spry1/2 DKO memory T cells displayed enhanced infiltration into infected tissue, demonstrating that absence of Spry1/2 can result in increased recall capacity. Upon adoptive transfer into naive hosts, Spry1/2 DKO memory T cells controlled Listeria monocytogenes infection better than WT cells. The enhanced formation of more functional Spry1/2 DKO memory T cells was associated with significantly reduced mTORC1 activity and glucose uptake. Reduced p-AKT, p-FoxO1/3a, and T-bet expression was also consistent with enhanced survival and memory accrual. Collectively, loss of Spry1/2 enhances the survival of effector CD8(+) T cells and results in the formation of more protective memory cells. Deleting Spry1/2 in antigen-specific CD8(+) T cells may have therapeutic potential for enhancing the survival and functionality of effector and memory CD8(+) T cells in vivo.
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关键词
CD8 T cells, memory, metabolism, survival, polyfunctional
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