Signaling Research Centers BIOSS and CIBSS; University of Freiburg, Freiburg, Germany.
Department of Immunology, Faculty of Biology, University of Freiburg, Freiburg, Germany.
Sci Adv. 2024 Mar 15;10(11):eadj2802. doi: 10.1126/sciadv.adj2802.
Development of T cells is controlled by the signal strength of the TCR. The scaffold protein kinase D-interacting substrate of 220 kilodalton (Kidins220) binds to the TCR; however, its role in T cell development was unknown. Here, we show that T cell-specific Kidins220 knockout (T-KO) mice have strongly reduced invariant natural killer T (iNKT) cell numbers and modest decreases in conventional T cells. Enhanced apoptosis due to increased TCR signaling in T-KO iNKT thymocytes of developmental stages 2 and 3 shows that Kidins220 down-regulates TCR signaling at these stages. scRNA-seq indicated that the transcription factor Aiolos is down-regulated in Kidins220-deficient iNKT cells. Analysis of an Aiolos KO demonstrated that Aiolos is a downstream effector of Kidins220 during iNKT cell development. In the periphery, T-KO iNKT cells show reduced TCR signaling upon stimulation with α-galactosylceramide, suggesting that Kidins220 promotes TCR signaling in peripheral iNKT cells. Thus, Kidins220 reduces or promotes signaling dependent on the iNKT cell developmental stage.
T 细胞的发育受 TCR 信号强度的控制。支架蛋白激酶 D 相互作用的 220 千道尔顿底物 (Kidins220) 与 TCR 结合；然而，其在 T 细胞发育中的作用尚不清楚。在这里，我们表明 T 细胞特异性 Kidins220 敲除 (T-KO) 小鼠的固有自然杀伤 T(iNKT)细胞数量明显减少，常规 T 细胞数量适度减少。由于 T-KO iNKT 胸腺细胞中 TCR 信号的增强导致凋亡增加表明，Kidins220 在这些阶段下调 TCR 信号。scRNA-seq 表明，转录因子 Aiolos 在 Kidins220 缺陷的 iNKT 细胞中下调。Aiolos KO 的分析表明，Aiolos 是 iNKT 细胞发育过程中 Kidins220 的下游效应物。在外周，T-KO iNKT 细胞在受到 α-半乳糖神经酰胺刺激时显示 TCR 信号减弱，表明 Kidins220 促进外周 iNKT 细胞中的 TCR 信号。因此，Kidins220 根据 iNKT 细胞发育阶段减少或促进信号。
