Blood Advances (Feb 2025)
Congenital T-cell activation impairs transitional-to-follicular B-cell maturation in humans
- Hugues Allard-Chamard,
- Kirsty Hillier,
- Michelle L. Ramseier,
- Alice Bertocchi,
- Naoki Kaneko,
- Katherine Premo,
- Grace Yuen,
- Marshall Karpel,
- Vinay S. Mahajan,
- Christina Tsekeri,
- Joseph S. Hong,
- Jean Vencic,
- Rory Crotty,
- Anish V. Sharda,
- Sara Barmettler,
- Emma Westermann-Clark,
- Jolan E. Walter,
- Musie Ghebremichael,
- Alex K. Shalek,
- Jocelyn R. Farmer,
- Shiv Pillai
Affiliations
- Hugues Allard-Chamard
- Ragon Institute of Mass General, Massachusetts Institute of Technology, and Harvard, Cambridge, MA; Division of Rheumatology, Faculté de médecine et des sciences de la santé de l'Université de Sherbrooke et Centre de Recherche Clinique Étienne-Le Bel, Sherbrooke, QC, Canada
- Kirsty Hillier
- Ragon Institute of Mass General, Massachusetts Institute of Technology, and Harvard, Cambridge, MA; Division of Pediatric Hematology-Oncology, Department of Pediatrics, Hassenfeld Children's Hospital at New York University Langone Health, New York University Grossman School of Medicine, New York, NY
- Michelle L. Ramseier
- Ragon Institute of Mass General, Massachusetts Institute of Technology, and Harvard, Cambridge, MA; Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA; Institute for Medical Engineering and Science, Koch Institute for Integrative Cancer Research, Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA; Broad Institute of Massachusetts Institute of Technology, and Harvard, Cambridge, MA
- Alice Bertocchi
- Ragon Institute of Mass General, Massachusetts Institute of Technology, and Harvard, Cambridge, MA
- Naoki Kaneko
- Ragon Institute of Mass General, Massachusetts Institute of Technology, and Harvard, Cambridge, MA; Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
- Katherine Premo
- Ragon Institute of Mass General, Massachusetts Institute of Technology, and Harvard, Cambridge, MA
- Grace Yuen
- Ragon Institute of Mass General, Massachusetts Institute of Technology, and Harvard, Cambridge, MA
- Marshall Karpel
- Ragon Institute of Mass General, Massachusetts Institute of Technology, and Harvard, Cambridge, MA; Cell Signaling Technology, Danvers, MA
- Vinay S. Mahajan
- Ragon Institute of Mass General, Massachusetts Institute of Technology, and Harvard, Cambridge, MA; Department of Pathology, Massachusetts General Hospital, Boston, MA
- Christina Tsekeri
- Ragon Institute of Mass General, Massachusetts Institute of Technology, and Harvard, Cambridge, MA
- Joseph S. Hong
- Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Boston, MA
- Jean Vencic
- Division of Rheumatology, Faculté de médecine et des sciences de la santé de l'Université de Sherbrooke et Centre de Recherche Clinique Étienne-Le Bel, Sherbrooke, QC, Canada
- Rory Crotty
- Department of Pathology, Brigham and Women's Hospital, Boston, MA
- Anish V. Sharda
- Division of Translational Hematology, Yale University School of Medicine, New Haven, CT
- Sara Barmettler
- Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Boston, MA
- Emma Westermann-Clark
- Division of Allergy and Immunology, Johns Hopkins All Children's Hospital, St. Petersburg, FL; Division of Allergy and Immunology, Morsani College of Medicine, University of South Florida, Tampa, FL
- Jolan E. Walter
- Division of Allergy and Immunology, Johns Hopkins All Children's Hospital, St. Petersburg, FL; Division of Allergy and Immunology, Morsani College of Medicine, University of South Florida, Tampa, FL; Division of Allergy and Immunology, Department of Pediatrics, Massachusetts General Hospital for Children, Boston, MA
- Musie Ghebremichael
- Ragon Institute of Mass General, Massachusetts Institute of Technology, and Harvard, Cambridge, MA
- Alex K. Shalek
- Ragon Institute of Mass General, Massachusetts Institute of Technology, and Harvard, Cambridge, MA; Institute for Medical Engineering and Science, Koch Institute for Integrative Cancer Research, Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA; Broad Institute of Massachusetts Institute of Technology, and Harvard, Cambridge, MA
- Jocelyn R. Farmer
- Ragon Institute of Mass General, Massachusetts Institute of Technology, and Harvard, Cambridge, MA; Clinical Immunodeficiency Program of Beth Israel Lahey Health, Division of Allergy and Immunology, Lahey Hospital & Medical Center, Burlington, MA; Correspondence: Jocelyn R. Farmer, Clinical Immunodeficiency Program of Beth Israel Lahey Health, Division of Allergy and Immunology, Lahey Hospital & Medical Center, 31 Mall Rd, Burlington, MA 01805;
- Shiv Pillai
- Ragon Institute of Mass General, Massachusetts Institute of Technology, and Harvard, Cambridge, MA; Shiv Pillai, Ragon Institute of Mass General, Massachusetts Institute of Technology, and Harvard, 600 Main St, Cambridge, MA 02139;
- Journal volume & issue
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Vol. 9,
no. 3
pp. 520 – 532
Abstract
Abstract: 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.
