Repertoire selection by pre-B-cell receptors and B-cell receptors, and genetic control of B-cell development from immature to mature B cells

Abstract

During B-cell development the surrogate light (SL) chain is selectively expressed in progenitor and precursor B cells during the developmental stages of D(H) to J(H) and V(H) to D(H)J(H) rearrangements. Approximately half of all muH chains produced by these rearrangements cannot pair with SL chains and cannot form a pre-B-cell receptor (pre-BCR). A spectrum of affinities between VpreB and individual V(H) domains generates preB cells with pre-BCR of different fitness which, in turn, determines the extent of the pre-B II-cell proliferation and the fidelity of allelic exclusion of the H chain locus. Once pre-BCR is expressed, SL chain expression is turned off. As pre-B II cells proliferate, SL is diluted out, thus limiting pre-BCR formation. As a consequence, pre-B II cells stop proliferating, become small and resting and begin to rearrange the L chain loci. Multiple rearrangements of the kappaL chain alleles are often detected in wild-type small pre-B II cells. Around 20% of the muH chain-expressing small pre-B II cells also express L chains but do not display the Ig on the surface. Hence, it is likely that not all L chains originally generated in resting pre-B II cells can pair with the muH chain previously present in that cell. The best fitting ones are selected preferentially to generate sIg+ B cells. Furthermore, the transition of immature B cells from the bone marrow to spleen and their development to mature cells appear as two separate steps controlled by different genes.

Tolerance checkpoints in B‐cell development: Johnny B good

“…Cells that have undergone a successful V to D-J recombination are selected, and the expression of the pre-BCR mediates their proliferative expansion [1,4,12,13,[25][26][27][28]. In mice lacking the surrogate light chain components, and thus unable to express the pre-BCR, this selection and expansion process fails to operate, resulting in the generation of fewer immature and mature B cells [1,[12][13][14]29]. Nevertheless, serum antibodies are at normal levels, and moreover, these mice are able to mount T-cell-dependent and -independent humoral immune responses [29].…”

“…At this stage of differentiation, the IgH chain loci are V to D-J rearranged and those that have done this successfully (synthesized a m-heavy (mH) chain) are positively selected within this compartment. This positive selection is mediated by the pre-BCR, which is composed of the mH chain and the surrogate light chain proteins Vpre-B and l5 [10][11][12][13][14][15]. Moreover, the pre-BCR induces a strong proliferation of these positively selected pre-B cells [12,13].…”

“…This positive selection is mediated by the pre-BCR, which is composed of the mH chain and the surrogate light chain proteins Vpre-B and l5 [10][11][12][13][14][15]. Moreover, the pre-BCR induces a strong proliferation of these positively selected pre-B cells [12,13]. A very recent report indicates that the pre-BCR might also be involved in the censoring of B-cell auto-reactivity [16].…”

Reconstructing immune phylogeny: new perspectives

“…and R. Haire, unpublished observations). Using a V-region-directed cloning technique in lamprey lymphocytes, a single gene was identified that resembles VpreB, which encodes a surrogate BCR light-chain component that is expressed early in lymphocyte ontogeny in higher vertebrates but does not participate directly in the function of the mature BCR 92 . The lamprey VpreB-like molecule might reflect the character of an early common ancestor that might or might not have mediated an immune function 93 .…”

Apoptosis in the development of the immune system

“…26,27 Following successful antigen receptor rearrangement, signals from the pre-T-cell receptors (pre-TCRs) or pre-B-cell receptors (preBCRs) signal the lymphocytes to promote the survival of the progenitors and induce their further differentiation. 28,29 T-lymphocyte progenitors that express a functional receptor are further subjected to both positive and negative selection to ensure that a functional receptor exists while eliminating those cells with self-reactive antigen receptors, which could be dangerous due to the potential for autoimmunity ( Figure 3). 30 When the avidity of interaction of the TCR and endogenous major histocompatibility complex (MHC) molecules is low, T-cell progenitors fail to be positively selected and undergo apoptosis.…”