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.