Aging is associated with remodeling of the immune system to enable the maintenance of life-long immunity. In the CD8⁺ T cell compartment, aging results in the expansion of highly differentiated cells that exhibit characteristics of cellular senescence. Here we found that CD27⁻CD28⁻CD8⁺ T cells lost the signaling activity of the T cell antigen receptor (TCR) and expressed a protein complex containing the agonistic natural killer (NK) receptor NKG2D and the NK adaptor molecule DAP12, which promoted cytotoxicity against cells that expressed NKG2D ligands. Immunoprecipitation and imaging cytometry indicated that the NKG2D–DAP12 complex was associated with sestrin 2. The genetic inhibition of sestrin 2 resulted in decreased expression of NKG2D and DAP12 and restored TCR signaling in senescent-like CD27⁻CD28⁻CD8⁺ T cells. Therefore, during aging, sestrins induce the reprogramming of non-proliferative senescent-like CD27⁻CD28⁻CD8⁺ T cells to acquire a broad-spectrum, innate-like killing activity.

衰老与免疫系统的重塑有关，以维持终生免疫力。在 CD8 ⁺ T 细胞区室中，衰老导致高度分化的细胞扩增，这些细胞表现出细胞衰老的特征。在这里，我们发现CD27 ^- CD28 ^- CD8 ⁺ T细胞失去了T细胞抗原受体（TCR）的信号活性，并表达含有激动性自然杀伤（NK）受体NKG2D和NK接头分子DAP12的蛋白质复合物，从而促进细胞毒性针对表达 NKG2D 配体的细胞。免疫沉淀和成像细胞术表明 NKG2D-DAP12 复合物与 sestrin 2 相关。 sestrin 2 的遗传抑制导致 NKG2D 和 DAP12 表达降低，并恢复衰老样 CD27 ⁻ CD28 ⁻ CD8 ⁺ T 细胞中的 TCR 信号传导。因此，在衰老过程中，sestrins 会诱导非增殖性衰老样 CD27 ^- CD28 ^- CD8 ⁺ T 细胞重新编程，以获得广谱、先天性杀伤活性。