Aiolos Supports TFH Cell Differentiation by Antagonizing the IL-2/STAT5 Signaling Pathway

Abstract CD4+ T follicular helper (TFH) cells are critical for the generation of robust humoral immune responses, as they provide help to B cells to support the generation of both pathogen-neutralizing antibodies and long-lived plasma cell populations. To date, the mechanisms underlying TFH differentiation are incompletely understood. Here, we identify the transcription factor Aiolos as a key regulator of TFH responses. We find that Aiolos expression is increased in TFH cell populations generated during influenza infection and that Aiolos deficiency results in compromised TFH cell differentiation and B cell helper activity. Mechanistically, loss of Aiolos results in diminished expression of TFH genes, including those encoding the key transcription factors Bcl-6, TCF-1, and Tox. Conversely, expression of genes associated with IL-2/STAT5 signaling, a known antagonist of the TFH gene program, were significantly elevated in Aiolos-deficient settings. Consistent with these data, antigen-specific Aiolos-deficient effector CD4+ T cell populations generated in response to influenza infection exhibited significantly elevated IL-2Rα surface expression. Together, our findings suggest that repression of IL-2/STAT5 signaling represents a novel mechanism by which Aiolos regulates the TFH gene program. These findings are important, as they provide critical insight that may ultimately be leveraged for the development of novel TFH-focused immunotherapies and strategies to improve vaccination approaches. Supported by a grant from the NIAID (NIH; R01 AI134972), funds through The Ohio State University College of Medicine, and funds through The Ohio State University College of Medicine Advancing Research in Infection and Immunity Fellowship Program