Divergent cytokine and transcriptional signatures control functional T follicular helper cell heterogeneity
CD4<sup>+</sup> T follicular helper (T<sub>FH</sub>) cells support tailored B cell responses against multiple classes of pathogens. To reveal how diverse T<sub>FH</sub> phenotypes are established, we profiled mouse T<sub>FH</sub> cells in response to viral, helminth and bacterial infection. We identified a core T<sub>FH</sub> signature that is distinct from CD4<sup>+</sup> T follicular regulatory and effector cells and identified pathogen-specific transcriptional modules that shape T<sub>FH</sub> function. Cytokine-transcriptional T<sub>FH</sub> programming demonstrated that type I interferon and TGFβ signaling direct individual T<sub>FH</sub> phenotypes to instruct B cell output. Cytokine-directed T<sub>FH</sub> transcriptional phenotypes are shared within human germinal centers, but distinct T<sub>FH</sub> 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<sub>FH</sub> phenotypes. Thus, we provide a comprehensive resource of T<sub>FH</sub> diversity in humans and mice to enable immune monitoring during infection and disease and to inform the development of context-specific vaccines.
Authors
- Stephen L. Nutt (ORCID: https://orcid.org/0000-0002-0020-6637)
- Angela Nguyen (ORCID: https://orcid.org/0000-0003-1610-515X)
- Katherine Kedzierska (ORCID: https://orcid.org/0000-0001-6141-335X)
- Ryan Munnings (ORCID: https://orcid.org/0000-0002-6911-7210)
- Nicola Harris (ORCID: https://orcid.org/0000-0003-2922-0210)
- Lauren Hailes
- Tabinda Hussain (ORCID: https://orcid.org/0000-0003-2672-2004)
- Melissa J. Davis (ORCID: https://orcid.org/0000-0003-4864-7033)
- Joanna R. Groom (ORCID: https://orcid.org/0000-0001-5251-7835)
- Lucy Cooper (ORCID: https://orcid.org/0000-0002-7153-5358)
- Amania A. Sheikh (ORCID: https://orcid.org/0000-0003-0769-2081)
- Laura K. Mackay (ORCID: https://orcid.org/0000-0002-8496-6632)
- Lauren J. Howson (ORCID: https://orcid.org/0000-0003-3522-4533)
- Katie L. Flanagan (ORCID: https://orcid.org/0000-0002-1575-1953)
- Lennard Dalit (ORCID: https://orcid.org/0000-0002-6159-6640)
- Colby Zaph (ORCID: https://orcid.org/0000-0002-9889-9848)
- Jennifer A. Juno (ORCID: https://orcid.org/0000-0002-9072-1017)
- Bailey E Williams (ORCID: https://orcid.org/0009-0007-9438-0778)
- Vanessa L. Bryant (ORCID: https://orcid.org/0000-0002-4697-7410)
- Nicole L. La Gruta (ORCID: https://orcid.org/0000-0001-5358-9363)
- Carolien E. van de Sandt (ORCID: https://orcid.org/0000-0002-4155-7433)
- Kim L. Good‐Jacobson (ORCID: https://orcid.org/0000-0003-1891-7274)
- Ming Z. M. Zheng (ORCID: https://orcid.org/0000-0002-5406-7425)
- Chin Wee Tan (ORCID: https://orcid.org/0000-0001-9695-7218)
- Aidil Zaini (ORCID: https://orcid.org/0000-0002-5144-9743)
- Alana Kirn
- Carolina Blanco Alvarado (ORCID: https://orcid.org/0009-0003-2451-3783)
Institutions
- University of Tasmania (AU)
- The Royal Melbourne Hospital (AU)
- The University of Queensland (AU)
- The University of Melbourne (AU)
- Walter and Eliza Hall Institute of Medical Research (AU)
- Discovery Institute (US)
- Westmead Hospital (AU)
- Peter Doherty Institute (AU)
- Monash University (AU)
- The University of Adelaide (AU)
- RMIT University (AU)
Publication Details
- Journal
- Nature Immunology
- Published
- 2025-09-09
- DOI
- https://doi.org/10.1038/s41590-025-02258-9
- Citations
- 6
- Primary Topic
- T-cell and B-cell Immunology
- Type
- article
- Field-Weighted Citation Impact
- 4.78