Hyperreactive B cells instruct their elimination by T cells to curb autoinflammation and lymphomagenesis.

Diehl C, Soberón V, Baygün S, Chu Y, Mandelbaum J, Kraus L, Engleitner T, Rudelius M, Fangazio M, Daniel C, Bortoluzzi S, Helmrath S, Singroul P, Gölling V, Osorio Barrios F, Seyhan G, Oßwald L, Kober-Hasslacher M, Zeng T, Öllinger R, Afzali AM, Korn T, Honarpisheh M, Lech M, Ul Ain Q, Pircher J, Imširović V, Jelenčić V, Wensveen FM, Passerini V, Bärthel S, Bhagat G, Dominguez-Sola D, Saur D, Steiger K, Rad R, Pasqualucci L, Weigert O, Schmidt-Supprian M (2025)

Publication Type: Journal article

Publication year: 2025

Journal

Immunity Elsevier

Book Volume: 58

Pages Range: 124-142.e15

Journal Issue: 1

DOI: 10.1016/j.immuni.2024.11.023

Abstract

B cell immunity carries the inherent risk of deviating into autoimmunity and malignancy, which are both strongly associated with genetic variants or alterations that increase immune signaling. Here, we investigated the interplay of autoimmunity and lymphoma risk factors centered around the archetypal negative immune regulator TNFAIP3/A20 in mice. Counterintuitively, B cells with moderately elevated sensitivity to stimulation caused fatal autoimmune pathology, while those with high sensitivity did not. We resolved this apparent paradox by identifying a rheostat-like cytotoxic T cell checkpoint. Cytotoxicity was instructed by and directed against B cells with high intrinsic hyperresponsiveness, while less reactive cells were spared. Removing T cell control restored a linear relationship between intrinsic B cell reactivity and lethal lymphoproliferation, lymphomagenesis, and autoinflammation. We thus identify powerful T cell-mediated negative feedback control of inherited and acquired B cell pathogenicity and define a permissive window for autoimmunity to emerge.

Involved external institutions

Technische Universität München (TUM) DE Germany (DE) Deutsches Krebsforschungszentrum (DKFZ) DE Germany (DE) Ludwig-Maximilians-Universität (LMU) DE Germany (DE) Sveučilište u Rijeci / University of Rijeka HR Croatia (HR) Klinikum der Universität München DE Germany (DE) Columbia University Irving Medical Center (CUIMC) US United States (USA) (US) Columbia University US United States (USA) (US) Icahn School of Medicine at Mount Sinai US United States (USA) (US)

How to cite

APA:

Diehl, C., Soberón, V., Baygün, S., Chu, Y., Mandelbaum, J., Kraus, L.,... Schmidt-Supprian, M. (2025). Hyperreactive B cells instruct their elimination by T cells to curb autoinflammation and lymphomagenesis. Immunity, 58(1), 124-142.e15. https://doi.org/10.1016/j.immuni.2024.11.023

MLA:

Diehl, Carina, et al. "Hyperreactive B cells instruct their elimination by T cells to curb autoinflammation and lymphomagenesis." Immunity 58.1 (2025): 124-142.e15.

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