Congenital T-cell activation impairs transitional-to-follicular B-cell maturation in humans
Patients with cytotoxic T-lymphocyte-associated protein 4 (CTLA4) deficiency exhibit profound humoral immune dysfunction, yet the basis for the B-cell defect is not known. We observed a marked reduction in transitional-to-follicular (FO) B-cell development in patients with CTLA4 deficiency, correlating with decreased CTLA4 function in regulatory T cells, increased CD40L levels in effector CD4+ T cells, and increased mammalian target of rapamycin complex 1 (mTORC1) signaling in transitional B cells (TrBs). Treatment of TrBs with CD40L was sufficient to induce mTORC1 signaling and inhibit FO B-cell maturation in vitro. Frequent cell-to-cell contacts between CD40L+ T cells and immunoglobulin D-positive CD27- B cells were observed in patient lymph nodes. FO B-cell maturation in patients with CTLA4 deficiency was partially rescued after CTLA4 replacement therapy in vivo. We conclude that functional regulatory T cells and the containment of excessive T-cell activation may be required for human TrBs to mature and attain metabolic quiescence at the FO B-cell stage.
Authors
- Alice Bertocchi (ORCID: https://orcid.org/0000-0002-3098-5643)
- Jean Vencic (ORCID: https://orcid.org/0000-0003-3525-1806)
- Naoki Kaneko (ORCID: https://orcid.org/0000-0002-1349-2660)
- Vinay S. Mahajan (ORCID: https://orcid.org/0000-0003-0814-2989)
- Jolán E. Walter (ORCID: https://orcid.org/0000-0002-6192-0703)
- Joseph Hong
- Musie Ghebremichael (ORCID: https://orcid.org/0000-0002-8572-1944)
- Grace J. Yuen (ORCID: https://orcid.org/0000-0002-3253-9575)
- Sara Barmettler (ORCID: https://orcid.org/0000-0001-8188-9187)
- Marshall Karpel (ORCID: https://orcid.org/0000-0002-9472-1524)
- Emma Westermann-Clark (ORCID: https://orcid.org/0000-0001-5562-234X)
- Shiv Pillai (ORCID: https://orcid.org/0000-0002-9905-875X)
- Hugues Allard‐Chamard (ORCID: https://orcid.org/0000-0001-7850-2658)
- Anish V. Sharda (ORCID: https://orcid.org/0000-0003-3856-4277)
- Michelle L. Ramseier (ORCID: https://orcid.org/0000-0002-9201-7656)
- Katherine Premo (ORCID: https://orcid.org/0000-0001-9214-659X)
- Kirsty Hillier (ORCID: https://orcid.org/0000-0001-7080-2293)
- Jocelyn R. Farmer (ORCID: https://orcid.org/0000-0003-4901-9848)
- Alex K. Shalek (ORCID: https://orcid.org/0000-0001-5670-8778)
- Christina Tsekeri
Institutions
- Broad Institute (US)
- Brigham and Women's Hospital (US)
- Université de Sherbrooke (CA)
- Harvard University (US)
- Johns Hopkins University (US)
- Kyushu Dental University (JP)
- University of South Florida (US)
- Ragon Institute of MGH, MIT and Harvard (US)
- Yale University (US)
- Massachusetts General Hospital (US)
- Johns Hopkins All Children's Hospital (US)
- Lahey Medical Center (US)
- IIT@MIT (US)
- Cell Signaling Technology (United States) (US)
- New York University (US)
- Massachusetts Institute of Technology (US)
Publication Details
- Journal
- Blood Advances
- Published
- 2024-12-03
- DOI
- https://doi.org/10.1182/bloodadvances.2024013267
- Citations
- 3
- Primary Topic
- T-cell and B-cell Immunology
- Type
- article
- Field-Weighted Citation Impact
- 0.72
Funders
- Bristol-Myers Squibb
- Pfizer
- AstraZeneca
- Broad Institute
- National Institutes of Health