T cell homeostasis and functional responsiveness require signals from self-peptide–major histocompatibility complex (self-pMHC) and cytokines, but the mechanisms controlling this signal integration are unknown. Using a conditional deletion of the T cell lineage-specific protein Themis, we show that Themis is required for the maintenance of peripheral CD8⁺ T cells and for proliferative CD8⁺ T cell responses to low-affinity pMHC aided by cytokines. Themis-deficient peripheral T cells show a phenotype indicative of reduced tonic signaling from self-pMHC, strongly suggesting that Themis is a positive regulator of T cell receptor signal strength in response to low-affinity self-pMHC in peripheral T cells. Signals from low-affinity pMHC and cytokines synergistically induce phosphorylation of the kinase Akt, metabolic changes and c-Myc transcription factor induction in CD8⁺ T cells only in the presence of Themis. This function of Themis is mediated through Shp1 phosphatase, as peripheral Themis and Shp1 double deletion rescues the peripheral CD8⁺ T cell maintenance.

T 细胞稳态和功能反应需要来自自身肽主要组织相容性复合体 (self-pMHC) 和细胞因子的信号，但控制这种信号整合的机制尚不清楚。通过条件性删除 T 细胞谱系特异性蛋白 Themis，我们表明 Themis 是维持外周 CD8 ⁺ T 细胞和增殖性 CD8 ^{+所必需的}在细胞因子的帮助下，T 细胞对低亲和力 pMHC 的反应。Themis 缺陷的外周 T 细胞表现出表明来自自身 pMHC 的强直信号减少的表型，强烈表明 Themis 是 T 细胞受体信号强度的正调节剂，以响应外周 T 细胞中的低亲和力自身 pMHC。来自低亲和力 pMHC 和细胞因子的信号仅在 Themis 存在的情况下协同诱导 CD8 ^{+ T 细胞中激酶 Akt 的磷酸化、代谢变化和 c-Myc 转录因子诱导。}Themis 的这一功能是通过 Shp1 磷酸酶介导的，因为外周 Themis 和 Shp1 双缺失可挽救外周 CD8 ⁺ T 细胞维持。