@article{66cb2ff47e6d4411ba157d7d867110ad,
title = "Aiolos represses CD4+ T cell cytotoxic programming via reciprocal regulation of TFH transcription factors and IL-2 sensitivity",
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.",
author = "Read, {Kaitlin A.} and Jones, {Devin M.} and Srijana Pokhrel and Hales, {Emily D.S.} and Aditi Varkey and Tuazon, {Jasmine A.} and Eisele, {Caprice D.} and Omar Abdouni and Abbey Saadey and Leonard, {Melissa R.} and Warren, {Robert T.} and Powell, {Michael D.} and Boss, {Jeremy M.} and Hemann, {Emily A.} and Yount, {Jacob S.} and Gang Xin and Ghoneim, {Hazem E.} and Lio, {Chan Wang J.} and Freud, {Aharon G.} and Collins, {Patrick L.} and Oestreich, {Kenneth J.}",
note = "Funding Information: The authors would like to thank all members of the Oestreich Lab, as well as colleagues in the Department of Microbial Infection and Immunity for constructive criticism. The authors would also like to thank the Cooperative Human Tissue Network of the Nationwide Children{\textquoteright}s Hospital (Columbus, OH) for providing human pediatric tonsil samples. The authors would like to thank members of the Lio laboratory (Heng-Yi Chen and Fang-Yun Lay) for their technical advice, and Dr. Haitao Wen for providing OT-II animals. Finally, the authors would like to thank members of the Yount laboratory (Ashley Zani, Adam Kenney, and Lizhi Zhang) for assistance with influenza virus preparation. This work was supported by grants from The National Institutes of Health AI134972 and AI127800 to K.J.O., AI156411 to P.L.C., CA199447 and CA208353 to A.G.F., K22CA241290 to C.J.L., F32AI161857 to M.D.P., and R01AI113021 to J.M.B. K.A.R. is supported by funding through The Ohio State University College of Medicine Advancing Research in Infection and Immunity Fellowship Program. J.A.T. is supported by funding through the Susan Huntington Dean{\textquoteright}s Distinguished University fellowship. J.A.T. and S.P. are supported by an Interdisciplinary Program in Microbe-Host Biology training grant; 1T32AI165391 awarded by NIH/NIAID. Finally, K.J.O. was also supported by funds from The Ohio State University College of Medicine and The Ohio State University Comprehensive Cancer Center. Funding Information: The authors would like to thank all members of the Oestreich Lab, as well as colleagues in the Department of Microbial Infection and Immunity for constructive criticism. The authors would also like to thank the Cooperative Human Tissue Network of the Nationwide Children{\textquoteright}s Hospital (Columbus, OH) for providing human pediatric tonsil samples. The authors would like to thank members of the Lio laboratory (Heng-Yi Chen and Fang-Yun Lay) for their technical advice, and Dr. Haitao Wen for providing OT-II animals. Finally, the authors would like to thank members of the Yount laboratory (Ashley Zani, Adam Kenney, and Lizhi Zhang) for assistance with influenza virus preparation. This work was supported by grants from The National Institutes of Health AI134972 and AI127800 to K.J.O., AI156411 to P.L.C., CA199447 and CA208353 to A.G.F., K22CA241290 to C.J.L., F32AI161857 to M.D.P., and R01AI113021 to J.M.B. K.A.R. is supported by funding through The Ohio State University College of Medicine Advancing Research in Infection and Immunity Fellowship Program. J.A.T. is supported by funding through the Susan Huntington Dean{\textquoteright}s Distinguished University fellowship. J.A.T. and S.P. are supported by an Interdisciplinary Program in Microbe-Host Biology training grant; 1T32AI165391 awarded by NIH/NIAID. Finally, K.J.O. was also supported by funds from The Ohio State University College of Medicine and The Ohio State University Comprehensive Cancer Center. Publisher Copyright: {\textcopyright} 2023, The Author(s).",
year = "2023",
month = dec,
doi = "10.1038/s41467-023-37420-0",
language = "English",
volume = "14",
journal = "Nature Communications",
issn = "2041-1723",
number = "1",
}