Divergent cytokine and transcriptional signatures control functional T follicular helper cell heterogeneity.

CD4 T follicular helper (T) cells support tailored B cell responses against multiple classes of pathogens. To reveal how diverse T phenotypes are established, we profiled mouse T cells in response to viral, helminth and bacterial infection. We identified a core T signature that is distinct from CD4 T follicular regulatory and effector cells and identified pathogen-specific transcriptional modules that shape T function. Cytokine-transcriptional T programming demonstrated that type I interferon and TGFβ signaling direct individual T phenotypes to instruct B cell output. Cytokine-directed T transcriptional phenotypes are shared within human germinal centers, but distinct T phenotypes dominate between donors and following immune challenge or in antibody-mediated disease. Finally, we identified new cell surface markers that align with distinct T phenotypes. Thus, we provide a comprehensive resource of T diversity in humans and mice to enable immune monitoring during infection and disease and to inform the development of context-specific vaccines.