B cells and CD5

Unlike T cells, CD5 is present on only some B cells and there is now strong evidence that this is a marker which identifies a normal B cell subpopulation (B1 cells), the size of which is genetically regulated. This population is different in origin, and can be distinguished from, conventional B cells responsible for most of the antibodies specific for exogenous antigens. In mice, B1 cells are self-renewing.

Both murine and human studies have indicated that B1 cells have minimal mutation of their rearranged immunoglobulin genes. They are responsible for the production of polyreactive and autoreactive antibodies and give rise to the so-called 'natural antibodies' present in normal serum. In this regard, elevated levels of CD5' B cells have been described in a plethora of autoimmune diseases in man including rheumatoid arthritis, primary Sjogren's syndrome, systemic lupus erythematous, Graves' disease, diabetes and many more. The significance of this is at present unclear. The presence of CD5 on human CLL cells and the polyreactive nature of antibodies programmed by these cells indicates that these malignant B cell tumors, are derived from this particular B cell subpopulation.

It is likely that normal B1 cells can act as 'antigen-presenting cells', using their polyreactive receptors to take in antigens for processing and presentation with surface major histocompatibility complex (MHC) class II molecules.

Identification of CD5 as a lineage marker has recently been challenged in experiments with murine and human cells. Expression of CD5 can be induced on murine splenic B cells (mostly B2 cells) following activation. In humans, B cells activated by phorbol ester treatment express CD5, and IL-4 has been shown to downregulate this molecule on the surface of these cells.

Taking these data together, it is possible that classical B1 cells prominent in early life are antigen-presenting cells and are a separate lineage representing germline encoded antibodies, many of which are activated through recognition of self antigen in vivo. Other B cells (B2 cells) appear to be capable of being induced to express CD5. The function of CD5 on these two B cell types may be different. The function of CD5 molecules on B cells has recently been addressed and there is now substantial evidence for its role in regulating B cell activity. CD5 is part of the B cell receptor complex as shown by capping and co-capping studies. Cross-linking of CD5 on B cells by monoclonal antibodies has a profound effect on stimulation of B cells through the antigen-specific immunoglobulin M (IgM) receptor. In mice, stimulation of peritoneal B1 cells with anti-IgM results in apoptosis. This is inhibited in CD5-deficient (CD5 knockout) mice. Cross-linking of CD5 in normal wild-type mice rescues the cells from anti-IgM-induced apoptosis and leads to proliferation of these cells. A similar effect is seen with human tonsillar CD5+ B cells in the presence of IL-2. Direct stimulation of CD5 on human tonsillar B cells alone can also stimulate apoptosis but different biochemical pathways appear to be used compared with induction of apoptosis via anti-IgM. The physiological relevance of these latter observations is currently unknown.

Recent data have suggested that in mice, one of the signal transduction activators of transcription (STAT3) is constitutively activated in B1 cells but not in unmanipulated B2 cells. This may play a role in B cell antigen-specific signaling and its constitutive activation, associated with the intrinsic proliferative nature of this population.

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