Congenital T-cell activation impairs transitional-to-follicular B-cell maturation in humans
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...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-02-01
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| Series: | Blood Advances |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2473952924006918 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Hugues Allard-Chamard |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-c45035a308ba4271a56a8f506473a1b7 |
| institution | Kabale University |
| issn | 2473-9529 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Blood Advances |
| spelling | doaj-art-c45035a308ba4271a56a8f506473a1b72025-01-30T05:14:48ZengElsevierBlood Advances2473-95292025-02-0193520532Congenital T-cell activation impairs transitional-to-follicular B-cell maturation in humansHugues Allard-Chamard0Kirsty Hillier1Michelle L. Ramseier2Alice Bertocchi3Naoki Kaneko4Katherine Premo5Grace Yuen6Marshall Karpel7Vinay S. Mahajan8Christina Tsekeri9Joseph S. Hong10Jean Vencic11Rory Crotty12Anish V. Sharda13Sara Barmettler14Emma Westermann-Clark15Jolan E. Walter16Musie Ghebremichael17Alex K. Shalek18Jocelyn R. Farmer19Shiv Pillai20Ragon 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, CanadaRagon 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, NYRagon 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, MARagon Institute of Mass General, Massachusetts Institute of Technology, and Harvard, Cambridge, MARagon 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, JapanRagon Institute of Mass General, Massachusetts Institute of Technology, and Harvard, Cambridge, MARagon Institute of Mass General, Massachusetts Institute of Technology, and Harvard, Cambridge, MARagon Institute of Mass General, Massachusetts Institute of Technology, and Harvard, Cambridge, MA; Cell Signaling Technology, Danvers, MARagon Institute of Mass General, Massachusetts Institute of Technology, and Harvard, Cambridge, MA; Department of Pathology, Massachusetts General Hospital, Boston, MARagon Institute of Mass General, Massachusetts Institute of Technology, and Harvard, Cambridge, MADivision of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Boston, MADivision 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, CanadaDepartment of Pathology, Brigham and Women's Hospital, Boston, MADivision of Translational Hematology, Yale University School of Medicine, New Haven, CTDivision of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Boston, MADivision 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, FLDivision 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, MARagon Institute of Mass General, Massachusetts Institute of Technology, and Harvard, Cambridge, MARagon 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, MARagon 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;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;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.http://www.sciencedirect.com/science/article/pii/S2473952924006918 |
| spellingShingle | 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 Congenital T-cell activation impairs transitional-to-follicular B-cell maturation in humans Blood Advances |
| title | Congenital T-cell activation impairs transitional-to-follicular B-cell maturation in humans |
| title_full | Congenital T-cell activation impairs transitional-to-follicular B-cell maturation in humans |
| title_fullStr | Congenital T-cell activation impairs transitional-to-follicular B-cell maturation in humans |
| title_full_unstemmed | Congenital T-cell activation impairs transitional-to-follicular B-cell maturation in humans |
| title_short | Congenital T-cell activation impairs transitional-to-follicular B-cell maturation in humans |
| title_sort | congenital t cell activation impairs transitional to follicular b cell maturation in humans |
| url | http://www.sciencedirect.com/science/article/pii/S2473952924006918 |
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