Aiolos represses CD4+ T cell cytotoxic programming via reciprocal regulation of TFH transcription factors and IL-2 sensitivity

• Published in: Nature communications Vol. 14; no. 1; pp. 1652 - 18
• Main Authors: Read, Kaitlin A., Jones, Devin M., Pokhrel, Srijana, Hales, Emily D. S., Varkey, Aditi, Tuazon, Jasmine A., Eisele, Caprice D., Abdouni, Omar, Saadey, Abbey, Leonard, Melissa R., Warren, Robert T., Powell, Michael D., Boss, Jeremy M., Hemann, Emily A., Yount, Jacob S., Xin, Gang, Ghoneim, Hazem E., Lio, Chan-Wang J., Freud, Aharon G., Collins, Patrick L., Oestreich, Kenneth J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24.03.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 13/21; 13/31; 14/1; 38; 38/15; 38/77; 38/88; 38/91; 631/250/127/1213; 631/250/1619/554; 631/250/1619/554/1898; 631/250/2502; 64/60; Antibodies; CD4 antigen; CD8 antigen; Cell differentiation; Cytotoxicity; Gene regulation; Humanities and Social Sciences; Interleukin 2; Interleukin 2 receptors; Lymphocytes; Lymphocytes T; multidisciplinary; Programming; Science; Science (multidisciplinary); Sensitivity enhancement; Stat5 protein; Transcription factors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-37420-0

During intracellular infection, T follicular helper (T FH ) and T helper 1 (T H 1) cells promote humoral and cell-mediated responses, respectively. Another subset, CD4-cytotoxic T lymphocytes (CD4-CTLs), eliminate infected cells via functions typically associated with CD8 + T cells. The mechanisms underlying differentiation of these populations are incompletely understood. Here, we identify the transcription factor Aiolos as a reciprocal regulator of T FH and CD4-CTL programming. We find that Aiolos deficiency results in downregulation of key T FH transcription factors, and consequently reduced T FH differentiation and antibody production, during influenza virus infection. Conversely, CD4-CTL programming is elevated, including enhanced Eomes and cytolytic molecule expression. We further demonstrate that Aiolos deficiency allows for enhanced IL-2 sensitivity and increased STAT5 association with CD4-CTL gene targets, including Eomes, effector molecules, and IL2Ra. Thus, our collective findings identify Aiolos as a pivotal regulator of CD4-CTL and T FH programming and highlight its potential as a target for manipulating CD4 + T cell responses. The regulation and direction of CD4 + T cells into phenotypic and functional lineages is coordinated by a complex set of mechanisms. Here the authors show a role for Aiolos as a regulator of the CD4 + cytotoxic and T follicular helper lineages.