Central B-cell tolerance: where selection begins

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.

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 V_HD_HJ_H 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 V_H, D_H, and Vκ gene segments in the actual Ig loci.

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 IgM^b congenic and 3-83Igi IgM^a congenic mice were mixed at equal proportion and injected into lethally irradiated recipient mice of H-2^d and H-2^b genetic backgrounds. The frequency of IgM^a and IgM^b 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-K^b 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-2^b), and relative to nonautoreactive mice (H-2^d). The blue rectangle indicates the experimental findings.

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.

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.

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.