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

Kaitlin A. Read, Devin M. Jones, Srijana Pokhrel, Emily D. S. Hales, Aditi Varkey, Jasmine A. Tuazon, Caprice D. Eisele, Omar Abdouni, Abbey Saadey, Melissa R. Leonard, Robert T. Warren, Michael D. Powell, Jeremy M. Boss, Emily A. Hemann, Jacob S. Yount, Gang Xin, Hazem E. Ghoneim, Chan-Wang J. Lio, Aharon G. Freud, Patrick L. Collins and Kenneth J. Oestreich ()
Additional contact information
Kaitlin A. Read: The Ohio State University College of Medicine and Wexner Medical Center
Devin M. Jones: The Ohio State University College of Medicine and Wexner Medical Center
Srijana Pokhrel: The Ohio State University College of Medicine and Wexner Medical Center
Emily D. S. Hales: The Ohio State University College of Medicine and Wexner Medical Center
Aditi Varkey: The Ohio State University College of Medicine and Wexner Medical Center
Jasmine A. Tuazon: The Ohio State University College of Medicine and Wexner Medical Center
Caprice D. Eisele: Biomedical Sciences Graduate Program
Omar Abdouni: The Ohio State University College of Medicine and Wexner Medical Center
Abbey Saadey: The Ohio State University College of Medicine and Wexner Medical Center
Melissa R. Leonard: The Ohio State University College of Medicine and Wexner Medical Center
Robert T. Warren: The Ohio State University College of Medicine and Wexner Medical Center
Michael D. Powell: Emory University School of Medicine
Jeremy M. Boss: Emory University School of Medicine
Emily A. Hemann: The Ohio State University College of Medicine and Wexner Medical Center
Jacob S. Yount: The Ohio State University College of Medicine and Wexner Medical Center
Gang Xin: The Ohio State University College of Medicine and Wexner Medical Center
Hazem E. Ghoneim: The Ohio State University College of Medicine and Wexner Medical Center
Chan-Wang J. Lio: The Ohio State University College of Medicine and Wexner Medical Center
Aharon G. Freud: The Ohio State University College of Medicine and Wexner Medical Center
Patrick L. Collins: The Ohio State University College of Medicine and Wexner Medical Center
Kenneth J. Oestreich: The Ohio State University College of Medicine and Wexner Medical Center

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract During intracellular infection, T follicular helper (TFH) and T helper 1 (TH1) 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 TFH and CD4-CTL programming. We find that Aiolos deficiency results in downregulation of key TFH transcription factors, and consequently reduced TFH 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 TFH programming and highlight its potential as a target for manipulating CD4+ T cell responses.

Date: 2023
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DOI: 10.1038/s41467-023-37420-0

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