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Human lymphoma mutations reveal CARD11 as the switch between self-antigen-induced B cell death or proliferation and autoantibody production


Jeelall, YS; Wang, JQ; Law, HD; Domaschenz, H; Fung, HKH; Kallies, A; Nutt, SL; Goodnow, CC; Horikawa, K
2012-10-22
JOURNAL OF EXPERIMENTAL MEDICINE
Journal Article
209
11
1907-1917
Self-tolerance and immunity are actively acquired in parallel through a poorly understood ability of antigen receptors to switch between signaling death or proliferation of antigenbinding lymphocytes in different contexts. It is not known whether this tolerance-immunity switch requires global rewiring of the signaling apparatus or if it can arise from a single molecular change. By introducing individual CARD11 mutations found in human lymphomas into antigen-activated mature B lymphocytes in mice, we find here that lymphoma-derived CARD11 mutations switch the effect of self-antigen from inducing B cell death into T cell-independent proliferation, Blimp1-mediated plasmablast differentiation, and autoantibody secretion. Our findings demonstrate that regulation of CARD11 signaling is a critical switch governing the decision between death and proliferation in antigen-stimulated mature B cells and that mutations in this switch represent a powerful initiator for aberrant B cell responses in vivo.
ROCKEFELLER UNIV PRESS
CHRONIC LYMPHOCYTIC-LEUKEMIA; RECEPTOR; MICE; ACTIVATION; GENOME; NICHES; GENE; BAFF; EXPRESSION; APOPTOSIS
Molecular Immunology
10.1084/jem.20112744
The Rockefeller University Press, doi: 10.1084/jem.20112744 © 2012 Jeelall et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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Creation Date 2012-10-22 12:00:00