Kidins220 and Aiolos promote thymic iNKT cell development by reducing TCR signals

• Published in: Science advances Vol. 10; no. 11; p. eadj2802
• Main Authors: Herr, Laurenz A, Fiala, Gina J, Sagar, Schaffer, Anna-Maria, Hummel, Jonas F, Zintchenko, Marina, Raute, Katrin, Velasco Cárdenas, Rubí M-H, Heizmann, Beate, Ebert, Karolina, Fehrenbach, Kerstin, Janowska, Iga, Chan, Susan, Tanriver, Yakup, Minguet, Susana, Schamel, Wolfgang W
• Format: Journal Article
• Language: English
• Published: United States 15.03.2024
• Subjects: Animals; Cell Differentiation; Gene Expression Regulation; Ikaros Transcription Factor - metabolism; Membrane Proteins - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Natural Killer T-Cells - metabolism; Receptors, Antigen, T-Cell - metabolism; Signal Transduction; Thymus Gland - cytology; Thymus Gland - metabolism
• ISSN: 2375-2548; 2375-2548
• 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.