Aiolos modulates the TFH and CD4-CTL differentiation programs via reciprocal regulation of the Zfp831/TCF-1/Bcl-6 axis and CD25

Effective immunity to influenza virus and other respiratory viruses requires the generation of CD4 + T cell subsets that coordinate multiple aspects of the immune response. These subsets include T follicular helper (T FH ) and T helper 1 (T H 1) cells, which promote humoral and cell-mediated responses, respectively. A third population, CD4 + cytotoxic T lymphocytes (CD4-CTLs) facilitates clearance of infection via mechanisms normally associated with CD8 + T cells. Here, we identify the transcription factor Aiolos as a regulator of T FH and CD4-CTL responses. We demonstrate that Aiolos deficiency compromises T FH differentiation and antibody production during influenza virus infection. Conversely, we find that CD4 + T cells acquire a cytotoxic-like program in the absence of Aiolos, including increased expression of the CTL-associated transcription factors Eomes and Blimp-1. We further show that while Aiolos positively regulates the T FH transcriptional regulators Zfp831, TCF-1 and Bcl-6, it also directly represses expression of IL-2Rα and IL-2/STAT5-driven expression of the cytotoxic gene program. Thus, our findings identify Aiolos as a pivotal regulator of T FH and CD4-CTL differentiation and highlight its potential as a target for manipulating CD4 + T cell humoral and cytotoxic responses.