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

During intracellular infection, T follicular helper (T) and T helper 1 (T1) 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 and CD4-CTL programming. We find that Aiolos deficiency results in downregulation of key T transcription factors, and consequently reduced T 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 programming and highlight its potential as a target for manipulating CD4 T cell responses.