Journal article
TRAF3 is critical for initial T follicular helper cell specification via coordination of the IL-6R/IL-2R-BCL6 signaling nexus
Science immunology, Vol.10(104), eadr0517
02/14/2025
DOI: 10.1126/sciimmunol.adr0517
PMCID: PMC12315785
PMID: 39951546
Abstract
CD4+ T follicular helper (TFH) cells are essential for orchestrating robust humoral immunity, yet the signals that initiate TFH cell differentiation are not fully understood. We identified that the adapter protein TRAF3 was required for TFH cell differentiation and function during systemic inflammatory infections. Loss of CD4+ T cell-intrinsic TRAF3 impaired chromatin remodeling and transcriptional programming essential for TFH cell initiation and instead augmented TH1 development and function. TRAF3-deficient CD4+ T cells exhibited altered interleukin-6 (IL-6) and IL-2 responsiveness, which were coupled to failures in BCL6 expression. Enforced expression of either IL-6 receptor or BCL6 or blockade of IL-2 signaling was sufficient to rescue TFH cell differentiation. Human CD4+ T cells lacking TRAF3 exhibited impaired TFH polarization, supporting a conserved mechanism by which TRAF3 regulates CD4+ T cell fate determination. Thus, TRAF3 functions at the nexus of cytokine, transcriptional, and epigenetic nodes that promote the TFH cell specification during infection.
Details
- Title: Subtitle
- TRAF3 is critical for initial T follicular helper cell specification via coordination of the IL-6R/IL-2R-BCL6 signaling nexus
- Creators
- Peng Shao - University of IowaRegina M Antonetti - University of IowaTina Arkee - Vanderbilt University Medical CenterEmma L Hornick - University of IowaHai Hui Xue - New Jersey Veterans Affairs Health Care System, East Orange, NJ, USAGail A Bishop - University of IowaNoah S Butler - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Science immunology, Vol.10(104), eadr0517
- DOI
- 10.1126/sciimmunol.adr0517
- PMID
- 39951546
- PMCID
- PMC12315785
- NLM abbreviation
- Sci Immunol
- ISSN
- 2470-9468
- eISSN
- 2470-9468
- Publisher
- AMER ASSOC ADVANCEMENT SCIENCE; WASHINGTON
- Grant note
- National institutes of health: ai125446, ai127481, ai167480, ai112579, ai121080, ai123107, t32ai007260 University of iowa holden comprehensive cancer center via its national institutes of health: P30ca086862 Department of Veterans affairs: BX005771 Office of Research and Development: BX005392
this work was supported by National institutes of health grants ai125446, ai127481, and ai167480 (to n.S.B.), ai112579 and ai121080 (to h.h.X.), ai123107 (to g.a.B.), and t32ai007260 (to e.l.h.); the University of iowa holden comprehensive cancer center via its national institutes of health grant P30ca086862 (to g.a.B.); the Department of Veterans affairs grant BX005771 (to h.h.X.); and the Office of Research and Development grant BX005392 (to g.a.B.). Some of the flow cytometer data presented herein were obtained at the Flow cytometry Facility, which is a carver college of medicine/holden comprehensive cancer center core research facility at the university of iowa. the facility is funded through user fees and the generous financial support of the carver college of medicine, holden comprehensive cancer center, and iowa city Veteran's administration medical center.-
- Language
- English
- Date published
- 02/14/2025
- Academic Unit
- Molecular Physiology and Biophysics; Microbiology and Immunology; President; Fraternal Order of Eagles Diabetes Research Center
- Record Identifier
- 9984791077302771
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