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Congenital T-cell activation impairs transitional-to-follicular B-cell maturation in humans.
- Source :
-
Blood advances [Blood Adv] 2025 Feb 11; Vol. 9 (3), pp. 520-532. - Publication Year :
- 2025
-
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.<br /> (© 2025 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
- Subjects :
- Humans
Cell Differentiation
Mechanistic Target of Rapamycin Complex 1 metabolism
T-Lymphocytes, Regulatory immunology
T-Lymphocytes, Regulatory metabolism
Signal Transduction
Female
Male
T-Lymphocytes immunology
T-Lymphocytes metabolism
CD40 Ligand metabolism
Lymphocyte Activation immunology
CTLA-4 Antigen metabolism
B-Lymphocytes immunology
B-Lymphocytes metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2473-9537
- Volume :
- 9
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Blood advances
- Publication Type :
- Academic Journal
- Accession number :
- 39626280
- Full Text :
- https://doi.org/10.1182/bloodadvances.2024013267