The development of lymphocytes from bone marrow stem cells involves commitment of hematopoietic pro genitors to the B or T cell lineage, the proliferation of these progenitors, the rearrangement and expression of antigen receptor genes, and selection events to pre serve and expand cells that express potentially useful antigen receptors (Fig. 1). These steps are common to B and T lymphocytes, even though B lymphocytes mature in the bone marrow and T lymphocytes mature in the thymus. Each of the processes that occurs during lymphocyte maturation plays a special role in the generation of the lymphocyte repertoire.

Fig1. Steps in maturation of lymphocytes. During their maturation, B and T lymphocytes go through cycles of proliferation and expression of antigen receptor proteins by gene recombination. Cells that fail to express intact, functional receptors die by apoptosis, because they do not receive the necessary survival signals. At the end of the process, the cells undergo positive and negative selection. The lymphocytes shown may be B or T cells.

• The maturation of common lymphoid progenitors in the bone marrow results in commitment to the B cell or T cell lineage. This commitment is associated with the activation of several lineage-specific transcription factors and increased accessibility of Ig and TCR genes to the gene recombination machinery, described later.

 • Developing lymphocytes undergo proliferation at several stages during their maturation. Proliferation of developing lymphocytes is necessary to ensure that an adequate number of cells will be available to express antigen receptors and mature into functionally competent lymphocytes. Survival and proliferation of the earliest lymphocyte precursors are stimulated mainly by growth factors that are produced by stromal cells in the bone marrow and the thymus. In humans, IL-7 maintains and expands the number of T lymphocyte progenitors before they express antigen receptors. The growth factors required for expansion of human B cell progenitors are not defined. This proliferative expansion generates a large pool of cells in which diverse antigen receptors may be produced. Even greater proliferation of the B and T cell lineages occurs after the developing lymphocytes have completed their first antigen receptor gene rearrangement and assembled a so-called preantigen receptor . This step is a quality control checkpoint in lymphocyte development that ensures preservation of cells with functional receptors.

• Lymphocytes are selected at multiple steps during their maturation to preserve useful specificities. Selection is based on the expression of intact antigen receptor components and what they recognize. As discussed later, many attempts to generate antigen receptors fail because of errors during the gene recombination process. Therefore, checkpoints are needed at which only cells that can express functional components of antigen receptors are selected to survive and proliferate. Prelymphocytes and immature lymphocytes that fail to express antigen receptor proteins die by apoptosis (see Fig. 1). The gene rearrangements in the developing lymphocytes randomly generate anti gen receptors with highly diverse specificities. Some of these may be incapable of recognizing antigens in the individual—for instance, if the TCR cannot recognize MHC alleles present in the individual. In order to preserve the T cells that will be functional, immature T cells are selected to survive only if they have some affinity for MHC molecules in the thymus. This process, called positive selection, ensures that cells that complete maturation will be capable of recognizing microbial peptides displayed by the same MHC molecules on APCs (which are the only MHC molecules these cells can normally encounter). Other anti gen receptors may strongly recognize certain peptides of self-proteins bound to self MHC, or strongly recognize self MHC regardless of the peptide displayed. Another selection process is needed to eliminate these potentially dangerous lymphocytes and prevent the development of autoimmune responses. The elimination of strongly self-reactive B and T lymphocytes is called negative selection.

The processes of B and T lymphocyte maturation and selection share some important features but also differ in many respects. We start with the central event that is common to both lineages: the recombination and expression of antigen receptor genes.