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Congenital T-cell activation impairs transitional-to-follicular B-cell maturation in humans.

Authors :
Allard-Chamard H
Hillier K
Ramseier ML
Bertocchi A
Kaneko N
Premo K
Yuen G
Karpel M
Mahajan VS
Tsekeri C
Hong JS
Vencic J
Crotty R
Sharda AV
Barmettler S
Westermann-Clark E
Walter JE
Ghebremichael M
Shalek AK
Farmer JR
Pillai S
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.)

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