B cells are derived from pluripotent haematopoietic stem cells and are produced in the human foetal liver at early stages of gestation, and in the bone marrow by weeks 14-17. B cells are at the centre of the adaptive humoral immune system and are responsible for mediating the production of antigen-specific immunoglobulin (Ig) directed against invasive pathogens (typically known as antibodies). The function of B cells was discovered in the 1960s by Max Cooper who demonstrated that antibody production was completely abrogated in irradiated chickens after surgical removal of the Bursa of Fabricius (the primary site of B-cell development in birds) from which the notation ‘B’ cell was derived. Several distinct B-cell subsets have been defined that possess distinct functions in both adaptive and innate humoral immune responses.
B-cell development and B-cell subsets (courtesy of Dr Andrew T. Vaughan)
In the pro-B cell stage in the bone marrow, Ig heavy chain gene rearrangement and expression occurs intracellularly in large pre-B cells, along with the components of the surrogate light chain. Together these form the pre-B cell receptor (pre-BCR) which relocates to the cell surface, signalling the cell to proliferate and differentiate into the small pre-B cell stage. Small pre-B cells upregulate the genes required for rearrangement of the Ig light chain, allowing the production of a complete functional BCR with a unique specificity that is expressed as IgM on the surface of immature B cells. Immature B cells then pass through a stage of negative selection to remove cells expressing a self-reactive BCR before exiting the bone marrow as short-lived transitional type 1 (T1) B cells. Thus, B cells experience both antigen-dependent and -independent phases of selection, tightly regulated through signalling events. T1 B cells migrate into B-cell follicles of the spleen or germinal centres of the cortex of the lymph nodes before differentiating into non-circulatory T2 B cells. The existence of a T3 B cell has also been proposed that may follow on from the T2 stage in B-cell development. After passage through the transitional stages, B cells become long-lived mature follicular cells and marginal zone (MZ) B cells of the spleen or cortical cells in lymph nodes.
Localisation of B-cells, similar to that in lymph nodes, occurs in secondary lymphoid tissues such as the Peyer’s patches of the small intestine where IgA-producing B cells are prevalent in the dome region adjacent to M-cells which sample antigen in the gut lumen and present it to lymphocytes. In addition to B2 and MZ B cells, mice have a third subset known as B1 B cells which are found in the peritoneal cavity, exist in the periphery, can migrate to sites of inflammation and are thought to be able to differentiate into a mononuclear phagocytic phenotype.
Regulatory B cells
B cells have a positive role in priming adaptive CD4+ T cells, but not CD8+ T cells. The magnitude of CD4+ T-cell responses is reduced upon pathogen challenge in B-cell deficient or -depleted mice. B cells are also able to negatively influence T-cell driven immune responses, giving rise to the recently proposed concept of regulatory B cells (Breg). Interleukin (IL-)10-secreting B cells with suppressive functions are referred to as B10 Bregs. B10 Bregs reduce disease severity in animal models, e.g. during experimental autoimmune encephalomyelitis (EAE), the secretion of IL-10 in mice has the effect of countering this T-cell-mediated autoimmune disease of the central nervous system. Bregs secreting IL10 or transforming growth factor β(TGFβ) have been identified in other animal models of auto-immunity, cancer and infection, supporting the concept that these cells have an important role in maintaining peripheral tolerance.
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