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 β-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.

鉴定促进细胞毒性T细胞功能强大和寿命长的新途径，对于对抗癌症和慢性感染的免疫治疗策略具有广阔的前景。我们表明，发芽的1和2（Spry1 / 2）分子调节记忆CD8 ⁺ T细胞的存活和功能。当将Spry1 / 2双敲除（DKO）卵清蛋白（OVA）特异性CD8 ⁺ T细胞（OT-I细胞）转移至在胰腺β岛中表达OVA的小鼠时，比WT OT-I细胞更有力的自身免疫性糖尿病。为了确定Spry1 / 2缺失对效应子和记忆CD8 ⁺ T细胞发育和功能的影响，我们使用了淋巴细胞性脉络膜脑膜炎病毒（LCMV）阿姆斯特朗的全身感染。Spry1 / 2 DKO LCMV gp33特定的P14 CD8 ⁺T细胞比WT细胞更能抵抗收缩，并能产生更多的多功能记忆T细胞。数量更多的Spry1 / 2 DKO记忆T细胞显示出对感染组织的浸润增强，表明Spry1 / 2的缺失会导致召回能力增强。在过继转移到幼稚宿主中后，Spry1 / 2 DKO记忆T细胞控制的单核细胞增生李斯特菌感染要比WT细胞更好。更多功能的Spry1 / 2 DKO记忆T细胞形成的增强与mTORC1活性和葡萄糖摄取的显着降低有关。降低的p-AKT，p-FoxO1 / 3a和T-bet的表达也与提高的生存率和记忆能力相一致。总的来说，Spry1 / 2的缺失增强了效应子CD8 ⁺的存活。T细胞并导致更多保护性记忆细胞的形成。在抗原特异性CD8 ⁺ T细胞中删除Spry1 / 2可能具有增强体内效应和记忆CD8 ⁺ T细胞存活和功能的治疗潜力。