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, 4 (4), a007146

Central B-cell Tolerance: Where Selection Begins

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Central B-cell Tolerance: Where Selection Begins

Roberta Pelanda et al. Cold Spring Harb Perspect Biol.

Abstract

The development of an adaptive immune system based on the random generation of antigen receptors requires a stringent selection process that sifts through receptor specificities to remove those reacting with self-antigens. In the B-cell lineage, this selection process is first applied to IgM(+) immature B cells. By using increasingly sophisticated mouse models, investigators have identified the central tolerance mechanisms that negatively select autoreactive immature B cells and prevent inclusion of their antigen receptors into the peripheral B-cell pool. Additional studies have uncovered mechanisms that promote the differentiation of nonautoreactive immature B cells and their positive selection into the peripheral B-cell population. These mechanisms of central selection are fundamental to the generation of a naïve B-cell repertoire that is largely devoid of self-reactivity while capable of reacting with any foreign insult.

Figures

Figure 1.
Figure 1.
Schematic representation of B-cell development and Ig loci in mice. Large pro-B cells initiate Ig gene rearrangement at the IgH locus. Expression of a H chain following a productive VHDHJH recombination event promotes the differentiation of large pre-B cells in which the expression of pre-BCR (H chain pairing with surrogate light chains) results in the clonal expansion of H chain-positive pre-B cells and the development of small pre-B cells. Expression of conventional L chains following productive rearrangements at the IgL chain loci in small pre-B cells promotes the development of a diverse population of IgM+ immature B cells, which then differentiate into IgM+IgD+ transitional B cells. The scheme of mouse Ig H, κ, and λ loci (not to scale) indicate the presence of V (white rectangles), D (black vertical lines), J (brown vertical lines; a dashed line indicates a nonfunctional element), and C (black rectangles; a gray rectangle indicates a nonfunctional element) gene segments. The scheme does not represent the number of VH, DH, and Vκ gene segments in the actual Ig loci.
Figure 2.
Figure 2.
Receptor editing in central B-cell selection. (A) Schematic representation of central B-cell tolerance. Immature B cells reacting with low to high avidity self-antigens undergo receptor editing, here represented by a secondary rearrangement at the Igκ allele. Immature B cells reacting with low avidity self-antigens can alternatively further differentiate and migrate into the spleen as anergic or ignorant B cells. Clonal deletion that occurs at a frequency that is presently unknown, but that is likely very low, is represented as a by-product of cells undergoing failed receptor editing. B cells encountering self-antigen in the periphery are represented undergoing peripheral deletion. (B) Experimental setup that tested the relative contribution of receptor editing and clonal deletion to central tolerance of developing 3-83Ig+ B cells (Halverson et al. 2004). Bone marrow cells from wild-type IgMb congenic and 3-83Igi IgMa congenic mice were mixed at equal proportion and injected into lethally irradiated recipient mice of H-2d and H-2b genetic backgrounds. The frequency of IgMa and IgMb B cells in the total B-cell population was measured in mixed bone marrow chimeras of the two experimental groups. The scheme on the right represents the expected outcomes of this analysis if all anti-Kb 3-83Ig+ B cells had undergone clonal deletion (top panel), receptor editing (middle panel), or a combination of either tolerance mechanism (bottom panel) in mice expressing the self-antigen (H-2b), and relative to nonautoreactive mice (H-2d). The blue rectangle indicates the experimental findings.
Figure 3.
Figure 3.
Receptor editing generates a small population of haplotype-included B cells. During receptor editing, a potential rearrangement at the second Igκ allele (intact arrow), or at the IgH or Igλ alleles, results in the generation of cells coexpressing two or more types of H and L chains. Some of these haplotype-included B cells are selected into the peripheral B-cell population expressing both autoreactive and nonautoreactive antibodies. Note that if receptor editing occurs on the original rearranged Igκ allele (dotted arrow), the previously used V-J sequence would be deleted.
Figure 4.
Figure 4.
Positive selection of nonautoreactive immature B cells into the peripheral B-cell compartment requires a threshold level of tonic BCR signaling. Differentiation of nonautoreactive immature B cells into transitional and mature B cells and entry into the peripheral B-cell population depends on a certain threshold of BCR expression and tonic BCR signaling, which is translated by the Ras-Mek-Erk signaling pathway. BAFFR expression correlates with BCR surface expression and tonic signaling, and BAFFR signaling contributes to the differentiation of immature into transitional B cells. The scheme is based on data from Rowland et al. 2010a,.
Figure 5.
Figure 5.
Autoreactive and nonautoreactive immature B cells undergo different fates during bone marrow selection. An autoreactive immature B-cell (on the left) experiences antigen-mediated BCR signaling in addition to the absence of tonic BCR signaling, and these events promote ongoing Ig gene rearrangements (receptor editing). Cytokines, such as IL-7, may be able to sustain limited cell survival during the editing process. A nonautoreactive immature B cell (on the right) experiences tonic BCR signaling in addition to BAFFR signaling, and these events promote further cell differentiation and selection into the peripheral B-cell compartment.

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