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

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