The Regulation of B cell development

III. Regulation of B cell development

B cell development occurs in fetal liver during embryonic development and is subsequently maintained in the bone marrow of adult animals. During B cell development, V(D)J recombinations take place at IgH and IgL chain loci in an ordered fashion to create a diverse repertoire of B cell receptors. The preB cell receptor (preBCR), composed of mH chains, invariant VpreB/l5 surrogate light (SL) chains and signal transducing module Iga/Igb heterodimers, plays critical roles during the early stage of B cell development. Deficiency of preBCR formation or its signaling results in severe impairment of B cell differentiation at the transition from proB to preB cell stages in both humans and mice.

 We have demonstrated that the Iga/Igb heterodimers are expressed on mH-negative proB cells and that the Igb cross-linking on proB cells in vivo induces early preB cell differentiation indistinguishable from that mediated by preBCR in normal B cell development (Immunity, 1997). This provided a powerful tool to examine the preBCR signaling and its effects on proliferation and differentiation of preB cells in vitro and in vivo. By using this system, we showed that the preBCR signals regulated the accessibility at IgH and IgL chain loci (J. Exp. Med., 2000) and that Src family kinases played crucial roles in preBCR signaling (Nat. Immunol., 2003).

 We have recently established a novel system to distinguish two different populations among mH-expressing preB cells in fetal liver and adult bone marrow: one expressing mH chains capable of forming preBCR, and the other expressing mH chains incapable of forming preBCR. The former but not the latter population is positively selected for expansion and further differentiation in both fetal liver and adult bone marrow (Int. Immunol. 2005). We also found that preB cells expressing mH chains with particular VH sequences are positively selected and amplified through the preBCR checkpoint during their development in fetal liver, and their descendent B cells are maintained in the splenic marginal zone even in adult life, perhaps as innate-type B cells (Int. Immunol. 2005).

 We demonstrated that preBCR assesses the quality of IgH chains and tunes the preB cell repertoire by delivering differential signals (J. Immuno, 2006). The level of surface preBCR expression varies among preB cells, depending on the ability of their mH chains to pair with SL chains. The higher the level of preBCR expression by preB cells, the stronger their preBCR signaling, and the better they proliferate and differentiate. Thus, the extent of survival, proliferation and differentiation of individual preB cells is primarily determined by the SL-pairing ability of their mH chains. Furthermore, IgH chains with higher potential to assemble with IgL chains appear to be positively selected and amplified through the assessment of their ability to pair with SL chains at the preBCR checkpoint prior to the assembly into the BCR. These results indicate that the preBCR tunes the preB cell repertoire by driving preferential expansion and differentiation of cells with higher quality of mH chains.

 We are currently investigating the molecular mechanisms underlying the regulation of preBCR expression and signaling. The failure of this regulation appears to result in immunodeficiency, autoimmune diseases or malignant formation.

References

  • Nagata, K., Nakamura, T., Kitamura, F., Kuramochi, S., Taki, S., Campbell, K. S. and Karasuyama, H.: The Iga/Igb heterodimer on m-negative proB cells is competent for transducing signals to induce early B cell differentiation. Immunity 7: 559-570, 1997. (PubMed)
  • Maki, K., Nagata, K., Kitamura, F., Takemori, T. and Karasuyama, H.: Immunoglobulin b signaling regulates locus accessibility for ordered Ig gene rearrangements. J. Exp. Med. 191: 1333-1340, 2000. (PubMed)
  • Saijo, K., Schmedt, C., Su, I-h., Karasuyama, H., Lowell, C.A., Reth, M., Adachi, T., Patke, A., Santana, A. and Tarakhovsky, A.: Essential role of Src-family protein tyrosine kinases in NF-kB activation during B cell development. Nature Immunol. 4: 274-279, 2003. (PubMed)
  • Kawano, Y., Yoshikawa, S., Minegishi, Y., and Karasuyama, H.: Selection of stereotyped VH81X-mH chains via preB cell receptor early in ontogeny and their conservation in adults by marginal zone B cells.Int. Immunol. 17: 857-867, 2005 (PubMed)
  • Kawano, Y., Yoshikawa, S., Minegishi, Y., and Karasuyama, H.: PreB cell receptor assesses the quality of IgH chains and tunes the preB cell repertoire by delivering differential signals. J. Immunol. 177: 2242-2249, 2006 (PubMed)