Early B Cell Development

Abstract

This chapter describes how B lymphocytes develop in the bone marrow from hematopoietic stem cells. Controlled by regulatory circuits of specific transcription factor activities, B cell precursors pass through defined stages of development. RAG-dependent rearrangement of V, D, and J heavy-chain gene segments starts in the pro-B cell stage. After the successful rearrangement of immunoglobulin gene segments, B cell precursors express functional immunoglobulin μ-heavy chains and proceed to the pre-B cell stage. As immunoglobulin light-chain gene segments are still to be rearranged, μ-heavy chains pair with V-pre-B and lambda5, two proteins that form the surrogate light chain. Together with two associated proteins termed Ig-α and Ig-β, the heavy and the surrogate light chains form the pre-B cell receptor (pre-BCR) complex. As pre-BCRs interact with each other, they do not need external ligands to induce receptor-dependent signaling. By activating signaling cascades downstream of phospholipase γ2 and of phosphoinositide 3-kinase, pre-BCR-induced signals regulate the rearrangement of the other immunoglobulin heavy-chain allele, pre-B cell proliferation, as well as the onset of immunoglobulin light-chain rearrangement. After the V and J gene segments of an immunoglobulin κ- or λ-light chain have been rearranged successfully, the precursor B cell starts to express IgM on its cell surface. If the IgM antibody molecules expressed by so-called immature B cells bind endogenous antigens expressed in the bone marrow, the immature B cells receive similar signals like pre-B cells from the pre-BCR. Thus, rearrangement of light-chain gene segments continues until the BCR has lost its self-reactivity as BCR-dependent signaling ceases. After this highly critical step of early B cell development, IgM+ immature B cells leave the bone marrow and move through the circulation to the spleen. In the meantime these cells develop further into transitional B cell and subsequently into mature follicular B cells or marginal zone B cells. While marginal zone B cells protect against infections with encapsulated bacteria, most of the naive follicular B cells share many characteristics with anergic B cells. These cells form the large repertoire of B cells that develop supported by T helper cells into long-lived plasma cells and memory B cells.