Optimal CXCR5 expression during Tfh maturation involves the Bhlhe40-Pou2af1 axis
The pair of transcription factors Bcl6-Blimp1 is well known for follicular T helper (Tfh) early cell fate determination; however, the mechanism(s) for late regulation of CXCR5 during Tfh migration into germinal centers (GCs) is still unclear. In this study, we uncovered another pair of transcription factors, Bhlhe40-Pou2af1, that regulate CXCR5 expression. Pou2af1 was specifically expressed in Tfh cells, whereas Bhlhe40 expression was found to be high in non-Tfh cells. Pou2af1 promoted Tfh formation and migration into a GC by upregulating CXCR5 but not Bcl6, while Bhlhe40 repressed this process by inhibiting Pou2af1 expression. RNA sequencing analysis of antigen-specific Tfh cells generated in vivo confirmed the role of Bhlhe40-Pou2af1 axis in regulating optimal CXCR5 expression. Thus, the regulation of CXCR5 expression and migration of Tfh cells into a GC involves a transcriptional regulatory circuit consisting of Bhlhe40 and Pou2af1, which does not affect the Bcl6-Blimp1 circuit that determines the Tfh cell fate.
Authors
- Dominic P. Golec (ORCID: https://orcid.org/0000-0002-2741-3302)
- Difeng Fang (ORCID: https://orcid.org/0000-0003-2105-6743)
- Danping Wei
- Tibor Z. Veres (ORCID: https://orcid.org/0000-0002-6980-8900)
- Hyunwoo Chung (ORCID: https://orcid.org/0000-0001-9103-0560)
- Sundar Ganesan (ORCID: https://orcid.org/0000-0003-1132-2016)
- Keji Zhao (ORCID: https://orcid.org/0000-0001-5559-6233)
- Pamela L. Schwartzberg (ORCID: https://orcid.org/0000-0001-6318-9187)
- Gangqing Hu (ORCID: https://orcid.org/0000-0001-5453-6888)
- Yaqiang Cao (ORCID: https://orcid.org/0000-0002-4665-1517)
- Jinfang Zhu (ORCID: https://orcid.org/0000-0002-0117-4745)
- Xiaoliang Zhu
- Ronald N. Germain (ORCID: https://orcid.org/0000-0003-1495-9143)
- Hirofumi Shibata (ORCID: https://orcid.org/0000-0002-8798-2611)
- Shuai Liu (ORCID: https://orcid.org/0000-0002-8814-9277)
- Chengyu Liu (ORCID: https://orcid.org/0000-0002-5136-9225)
- Xi Chen (ORCID: https://orcid.org/0000-0002-1570-6925)
- Zoey J Kline
Institutions
- National Institutes of Health (US)
- National Heart, Lung, and Blood Institute (US)
- National Institute of Allergy and Infectious Diseases (US)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-10-23
- DOI
- https://doi.org/10.1016/j.celrep.2025.116470
- Citations
- 1
- Primary Topic
- interferon and immune responses
- Type
- article
- Field-Weighted Citation Impact
- 0.80
Funders
- U.S. Department of Health and Human Services
- National Institutes of Health
- National Heart, Lung, and Blood Institute
- National Institute of Allergy and Infectious Diseases