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B cell receptor signal strength determines B cell fate

Abstract

B cell receptor (BCR)-mediated antigen recognition is thought to regulate B cell differentiation. BCR signal strength may also influence B cell fate decisions. Here, we used the Epstein-Barr virus protein LMP2A as a constitutively active BCR surrogate to study the contribution of BCR signal strength in B cell differentiation. Mice carrying a targeted replacement of Igh by LMP2A leading to high or low expression of the LMP2A protein developed B-1 or follicular and marginal zone B cells, respectively. These data indicate that BCR signal strength, rather than antigen specificity, determines mature B cell fate. Furthermore, spontaneous germinal centers developed in gut-associated lymphoid tissue of LMP2A mice, indicating that microbial antigens can promote germinal centers independently of BCR-mediated antigen recognition.

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Figure 1: LMP2A expression rescues the development of BCR-deficient B cells.
Figure 2: DHLMP2A mice generate follicular and marginal zone B cells, whereas VHLMP2A mice give rise to B-1 cells.
Figure 3: Proximal LMP2A signaling in VHLMP2A and DHLMP2A mature B cells.
Figure 4: Germinal centers in GALT but not spleens of DHLMP2A mice.
Figure 5: GALT germinal centers of DHLMP2A mice depend on intestinal bacteria and T cells and involve complement activation.
Figure 6: Spontaneous germinal centers in GALT of IgHHEL IgLHEL mice.

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Acknowledgements

We thank G. Esposito, ZY. Hao, A. Waisman, U. Zimber-Strobl and W. Hammerschmidt for discussions; T. Novobrantseva for sharing unpublished results and for critical reading of the manuscript; T. Schneider for providing IgHHEL IgLHEL mice; T.W. Behrens for B1-8hi;3-83κi mice; and S. Willms, A. Egert, A. Roth, C. Goettlinger, N. Barteneva, D. Ghitza and V. Dreier for technical assistance. Supported by the National Institutes of Health (CA098285-01A1 and CA92625; K.R.), the Volkswagen Foundation (K.R.) and the Human Frontier Science Program and the Cancer Research Institute (S.C.).

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Correspondence to Stefano Casola or Klaus Rajewsky.

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Casola, S., Otipoby, K., Alimzhanov, M. et al. B cell receptor signal strength determines B cell fate. Nat Immunol 5, 317–327 (2004). https://doi.org/10.1038/ni1036

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