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. 2011 Aug;41(8):2397-403.
doi: 10.1002/eji.201041344. Epub 2011 Jul 4.

Efficient generation of B lymphocytes by recognition of self-antigens

Cathrin Eschbach  1 , Martina P Bach, Ingrid Fidler, Roberta Pelanda, Fabian Köhler, Klaus Rajewsky, Hassan Jumaa
Affiliations

Efficient generation of B lymphocytes by recognition of self-antigens

Cathrin Eschbach et al. Eur J Immunol. 2011 Aug.

Abstract

Antibody diversity is generated by a random gene recombination process with the inherent risk of the production of autoreactive specificities. The current view suggests that B cells expressing such specificities are negatively selected at an early developmental stage. Using the knock-in model system of the 3-83 autoreactive B-cell antigen receptor (BCR) in combination with precursor-BCR (pre-BCR) deficiency, we show here that the 3-83 BCR mediates efficient generation of B cells in the presence, but not the absence, of a strongly recognized auto-antigen. Experiments with mixed bone marrow chimeras showed that combining the 3-83 BCR with the corresponding auto-antigen resulted in efficient reconstitution of B-cell development in immune-deficient mice. These results suggest that B cells are positively selected by recognition of self-antigens during developmental stages that precede receptor editing. Moreover, the data indicate that the pre-BCR functions as a specialized autoreactive BCR to initiate positive selection at a stage where the cells express immunoglobulin heavy but not light chains.

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Conflict of interest statement

Conflict of interest: The authors declare no financial or commercial conflict of interest.

Figures

Figure 1
Figure 1
The autoreactive BCR replaces the pre-BCR in B cell development. (A) Flow cytometric analysis of bone marrow (bm) cells from l5−/− and wild-type (WT) or (B) 3–83Hi/3–83κi/λ5−/− mice on different backgrounds: H-2d lacking and H-2b containing the auto-antigen. Numbers show the percentages of bone marrow cells in each quadrant. (C) Flow cytometric analysis of splenic cells of λ5−/−, WT and (D) 3–83Hi/3–83κi/λ5−/− mice on different backgrounds stained with anti-B220 versus anti-IgM. Numbers indicate percentages of B220+ cells. (E) Absolute numbers of total splenic B cells from the indicated mice were determined. For each group, at least three individuals were analyzed. Data represent mean+SD of total splenic B cells. ***indicates (p = 0.0002) in numbers of total splenic B cells. B cell numbers of WT mice (column 2) and 3–83Hi/3–83κi/λ5−/− mice on H-2b background (column 4) were not significantly different (p = 0.1761, Student’s t-test).
Figure 2
Figure 2
Autoreactivity restores pre-BCR deficiency in competitive BM chimeras. (A) Schematic illustration of hematopoietic stem cell (HSC) transfer into immune-deficient mice. GFP cassette inserted into the mb-1 gene, which encodes the BCR component Ig-α, was used to track WT B cells. (B, C) Flow cytometric analysis of bone marrow (bm) and splenic (sp) cells 5wk after HSC transfer. The background of the recipient Rag-2/γbC−/− mice is indicated. HSCs were injected in different ratios (1:1, 1:0.5, 0.5:1). In 0:0, PBS was injected as control. The percentages of GFP+ and GFP− cells are indicated. A total of 12 mice were analyzed (2 mice per HSC ratio on two different backgrounds).
Figure 3
Figure 3
Autoreactivity is required for efficient generation of B cells. (A) Schematic illustration of HSC transfer into immune-deficient mice. GFP expression was used to track B cells from expressing the non-autoreactive BCR containing the B1–8 HC. (B, C) Flow cytometric analysis of bone marrow (bm) and splenic (sp) cells 5wk after HSC transfer. The background of the recipient Rag-2/γC−/− mice is indicated. As in Fig. 2, different ratios (1:1, 1:0.5, 0.5:1) of HSCs or PBS were injected. (D) Flow cytometric analysis of CD19+ splenic B cells from two different mice on H-2b background. Cells were stained with anti-CD21 versus anti-CD23. Percentages of follicular (FO) and marginal zone (MZ) B cells are indicated. A total of 12 mice were analyzed (2 mice per HSC ratio on two different backgrounds).
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