Antigen and cytokine receptor signals guide the development of the naïve mature B cell repertoire

Abstract

Immature B cells are generated daily in the bone marrow tissue. More than half of the newly generated immature B cells are autoreactive and bind a self-antigen, while the others are nonautoreactive. A selection process has evolved on the one hand to thwart development of autoreactive immature B cells and, on the other hand, to promote further differentiation of nonautoreactive immature B cells into transitional and mature B cells. These negative and positive selection events are carefully regulated by signals that emanate from the antigen receptor, whether antigen-mediated or tonic, and are influenced by signals that are generated by receptors that bind cytokines, chemokines, and other factors produced in the bone marrow tissue. These signals, therefore, are the predominant driving forces for the generation of a B cell population that is capable of protecting the body from infections while maintaining self-tolerance. Here, we review recent findings from our group and others that describe how tonic antigen receptor signaling and bone marrow cytokines regulate the selection of immature B cells.

Fig. 1

Schematic representation of central B cell selection. B cell development in the bone marrow results in the generation of immature B cells each expressing a different antigen receptor. A fraction of immature B cells is autoreactive, binds self-antigens, and undergoes negative selection (tolerance). Immature B cells that do not bind self-antigens (nonautoreactive cells) continue their differentiation into transitional and mature B cells and are positively selected into the circulation and the peripheral lymphoid compartment

Fig. 2

A model for positive selection of immature B cells. Surface BCR levels vary on immature B cells depending on their developmental progression and avidity for self-antigen. Differentiation of immature B cells (IgM⁺) into transitional and mature B cells (IgM⁺IgD⁺) and entry into the peripheral B cell population depends on BCR expression and tonic BCR signaling. Tonic BCR signaling translates into Erk phosphorylation, and a threshold level of pErk may be necessary to set in motion these biological events. The cytokine IL-7 may be important for maintaining the survival of immature B cells while they attempt to reach the threshold level of BCR expression and tonic BCR signaling required for positive selection. Once the BCR has reached the threshold level for positive selection, BAFFR is also expressed and immature B cells react to available BAFF. BAFFR signaling contributes to the differentiation of immature B cells into transitional and mature B cells

Fig. 3

Autoreactive and nonautoreactive immature B cells display differential response to IL-7 and BAFF. a Relative il7r RNA levels in 3-83Ig⁺ autoreactive, nonautoreactive, and BCR-low immature B cells. Bone marrow B220⁺IgD⁻CD23⁻CD43⁻ immature B cells were sorted from nonautoreactive 3-83Igi,H-2^d (white bar), autoreactive 3-83Igi,Rag1^−/−,H-2^b (black bar), and 3-83Igi-low mice and subjected to whole genome microarray analyses. The bars represent the arithmetic mean and SD of the normalized processed signal for the il7r gene from three independent samples and microarrays reporting 3 different probes. The signals detected in autoreactive and low cells were normalized to those of nonautoreactive cells that were set to one. *p = 0.008 (two-sample randomization paired test). Additional information about this analysis and the mice can be found in [64]. b Survival of 3-83Ig⁺ autoreactive and nonautoreactive immature B cells in culture. Bone marrow immature B cells were sorted as B220⁺IgD⁻CD23⁻CD43⁻ from nonautoreactive 3-83Igi,H-2^d mice (white bar) and as B220⁺IgM⁻IgD⁻CD23⁻CD43⁻ from autoreactive 3-83Igi,H-2^b (black bar) mice. Sorted cells were cultured at equal numbers in complete medium with or without IL-7 or BAFF. After 3 days of culture, live and dead cells were counted following trypan blue staining. The bars represent the arithmetic mean and SD of live cell numbers from 3 independent experiments. The difference between autoreactive and nonautoreactive cells was not statistically significant at each condition, but the trend was the same in each of the three experiments. Additional information about the mice can be found in [75]