The nutrient-sensing mammalian target of rapamycin (mTOR) is integral to cell fate decisions after T cell activation. Sustained mTORC1 activity favors the generation of terminally differentiated effector T cells instead of follicular helper and memory T cells. This is particularly pertinent for T cell responses of older adults who have sustained mTORC1 activation despite dysfunctional lysosomes. Here, we show that lysosome-deficient T cells rely on late endosomes rather than lysosomes as an mTORC1 activation platform, where mTORC1 is activated by sensing cytosolic amino acids. T cells from older adults have an increased expression of the plasma membrane leucine transporter SLC7A5 to provide a cytosolic amino acid source. Hence, SLC7A5 and VPS39 deficiency (a member of the HOPS complex promoting early to late endosome conversion) substantially reduced mTORC1 activities in T cells from older but not young individuals. Late endosomal mTORC1 is independent of the negative-feedback loop involving mTORC1-induced inactivation of the transcription factor TFEB that controls expression of lysosomal genes. The resulting sustained mTORC1 activation impaired lysosome function and prevented lysosomal degradation of PD-1 in CD4⁺ T cells from older adults, thereby inhibiting their proliferative responses. VPS39 silencing of human T cells improved their expansion to pertussis and to SARS-CoV-2 peptides in vitro. Furthermore, adoptive transfer of CD4⁺ Vps39-deficient LCMV-specific SMARTA cells improved germinal center responses, CD8⁺ memory T cell generation, and recall responses to infection. Thus, curtailing late endosomal mTORC1 activity is a promising strategy to enhance T cell immunity.

雷帕霉素的营养感应哺乳动物靶标 (mTOR) 是 T 细胞激活后细胞命运决定不可或缺的一部分。持续的 mTORC1 活性有利于产生终末分化的效应 T 细胞，而不是滤泡辅助和记忆 T 细胞。这对于尽管溶酶体功能失调但仍持续激活 mTORC1 的老年人的 T 细胞反应尤为重要。在这里，我们展示了溶酶体缺陷型 T 细胞依赖晚期内体而不是溶酶体作为 mTORC1 激活平台，其中 mTORC1 通过检测胞质氨基酸被激活。来自老年人的 T 细胞质膜亮氨酸转运蛋白 SLC7A5 的表达增加，以提供胞质氨基酸来源。因此，SLC7A5 和 VPS39 缺陷（促进早期到晚期内体转换的 HOPS 复合物的成员）显着降低了来自老年人而非年轻人的 T 细胞中的 mTORC1 活性。晚期内体 mTORC1 与负反馈回路无关，该负反馈回路涉及 mTORC1 诱导的转录因子 TFEB 失活，该转录因子 TFEB 控制溶酶体基因的表达。由此产生的持续 mTORC1 激活损害了溶酶体功能并阻止了 CD4 中 PD-1 的溶酶体降解⁺来自老年人的 T 细胞，从而抑制他们的增殖反应。人类 T 细胞的VPS39沉默改善了它们在体外对百日咳和 SARS-CoV-2 肽的扩增。此外，CD4 ⁺ Vps39 缺陷型LCMV 特异性 SMARTA 细胞的过继转移改善了生发中心反应、CD8 ⁺记忆 T 细胞生成和对感染的回忆反应。因此，减少晚期内体 mTORC1 活性是增强 T 细胞免疫的有前途的策略。