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Receptor editing is the main mechanism of B cell tolerance toward membrane antigens

Abstract

Self-reactive B cells specific for ubiquitous membrane-bound autoantigens are eliminated in the bone marrow by two mechanisms of tolerance: receptor editing and clonal deletion. However, the relative contributions of clonal deletion and receptor editing to B cell tolerance in a polyclonal B cell population have not been established. Here we show that tolerance toward a membrane antigen–reactive B cell clone acts by receptor editing with very minimal cell loss. The capacity of receptor editing to rescue almost all autoreactive B cells from deletion relies on the availability of multiple joining light chain gene segments as substrate for secondary immunoglobulin light chain gene rearrangement and is independent of the affinity of the autoantigen and the presence of non-autoreactive B cells. Our data further suggest that clonal deletion is a default pathway that functions only when receptor editing has been exhausted.

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Figure 1: Receptor editing is an efficient mechanism of tolerance for B cells reactive with membrane-bound autoantigens.
Figure 2: Receptor editing efficiently eliminates the autoreactive κ chain.
Figure 3: Edited B cells are recruited to the spleen at rates equivalent to those of wild-type B cells.
Figure 4: A compromised ability or an inability to receptor edit leads to cell deletion.
Figure 5: The contribution of receptor editing to the B cell repertoire is not affected by autoantigen avidity.

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Acknowledgements

We thank K. Pape (University of Minnesota, Minneapolis, Minnesota) for the gift of anti-3-83κ and S. Liu for analyzing expression of CD19 in 3-83Igi, Rag1-deficient mice. We also thank P. Marrack for her constructive contributions during the writing of this manuscript; J. Cambier for critical reading of the manuscript; and F. Agenès (Institute Pasteur, Paris, France) for discussion that led to this work. This work was supported by the National Institutes of Health (AI052310 to R.P. and AI052157 to R.T.) and the Arthritis Foundation Colorado Chapter (R.P.).

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Correspondence to Roberta Pelanda.

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Halverson, R., Torres, R. & Pelanda, R. Receptor editing is the main mechanism of B cell tolerance toward membrane antigens. Nat Immunol 5, 645–650 (2004). https://doi.org/10.1038/ni1076

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