B cell development is a carefully regulated process that involves the sequential differentiation of hematopoietic stem cell precursors into immature and transitional B cells in the bone marrow, and subsequent maturation to mature naïve and memory subsets occurring in peripheral lymphoid organs (e.g., lymph nodes and spleen) (; ).1–3, 8, 9
Development of the B cell lineage.*
Overview of B cell development (see text for details and abbreviations).
B cell development begins in the bone marrow with the pluripotent hematopoietic stem cell, which first differentiates into a multipotent progenitor cell. The latter cell interacts with bone marrow stromal cells to differentiate into the common lymphocyte progenitor, which gives rise to both T cell progenitors and the earliest B-lineage cell, the pro-B cell. Pro-B cells are characterized by the expression of the first B cell-specific surface marker, CD22. Immunoglobulin gene rearrangement begins in pro-B cells; this is a key event in the development of a diverse antibody repertoire. The recombinase-activating gene-encoded enzymes, RAG1and RAG2, are essential for this process, as well as for T cell receptor gene rearrangement in T cells; thus, RAG mutations lead to a form of severe combined immunodeficiency. The next developmental stage, the pre-B cell, is characterized by the completed rearrangement of the heavy μ chain paired with the surrogate light chain on the cell surface (termed the pre-B cell receptor), along with expression of CD19 and later CD20. The pre- B cell receptor (BCR) is a critical checkpoint for the regulation of B cell development, since its expression and functional signaling are required for cell expansion and further differentiation. The X chromosome-encoded cytoplasmic Bruton’s tyrosine kinase (BTK) plays a key role in pre-BCR signaling.
Successful light chain recombination characterizes progression to the immature B cell stage, allowing surface expression of complete IgM molecules. This is another defining moment in the life of the B cell; from now on, its development is dependent upon cognate recognition of antigen. Antigen-specific negative selection, receptor editing, and clonal deletion begin to control autoreactivity (i.e., “immune tolerance to self” is established). Despite the typical apoptosis of autoreactive B cells in the bone marrow, a significant fraction of them may proceed unchecked into the peripheral repertoire, creating the need for additional censoring at later stages.10, 11
Although more than 107
B cell precursors begin their development each day, only a few percent will survive and emerge into the peripheral blood as transitional B cells ().
After passing the transitional stage, the human mature B cell compartment consists of multiple cell populations including circulating B cells, follicular naïve, marginal zone, and diverse memory cell subsets.12, 13
Mature B cells express surface IgM, IgD, CD19, and CD20; their survival depends upon recognition of their cognate antigen and subsequent differentiation. Naïve follicular B cells that are successfully activated by antigen and T cell-derived signals in spleen or lymph node can give rise to the GCs, specialized structures crucial for class switch recombination (CSR) and somatic hypermutation (SHM), which in turn are responsible for the acquisition of different immunoglobulin isotypes, increased antigen specificity, and long-lived memory and plasma cell generation. Memory B cells are marked by surface expression of CD27.