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

Abstract 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.