Quorum sensing contributes to activated IgM-secreting B cell homeostasis.

Maintenance of plasma IgM levels is critical for immune system function and homeostasis in humans and mice. However, the mechanisms that control homeostasis of the activated IgM-secreting B cells are unknown. After adoptive transfer into immune-deficient hosts, B lymphocytes expand poorly, but fully reconstitute the pool of natural IgM-secreting cells and circulating IgM levels. By using sequential cell transfers and B cell populations from several mutant mice, we were able to identify novel mechanisms regulating the size of the IgM-secreting B cell pool. Contrary to previous mechanisms described regulating homeostasis, which involve competition for the same niche by cells having overlapping survival requirements, homeostasis of the innate IgM-secreting B cell pool is also achieved when B cell populations are able to monitor the number of activated B cells by detecting their secreted products. Notably, B cell populations are able to assess the density of activated B cells by sensing their secreted IgG. This process involves the FcγRIIB, a low-affinity IgG receptor that is expressed on B cells and acts as a negative regulator of B cell activation, and its intracellular effector the inositol phosphatase SHIP. As a result of the engagement of this inhibitory pathway, the number of activated IgM-secreting B cells is kept under control. We hypothesize that malfunction of this quorum-sensing mechanism may lead to uncontrolled B cell activation and autoimmunity.

Positive selection of B cells expressing low densities of self-reactive BCRs.

B cell tolerance or autoimmunity is determined by selective events. Negative selection of self-reactive B cells is well documented and proven. In contrast, positive selection of conventional B cells is yet to be firmly established. Here, we demonstrate that developing self-reactive B cells are not always highly sensitive to the deletion mechanisms imposed by membrane-bound self-antigens. At low amounts, membrane-bound antigens allow survival of B cells bearing a single high affinity self-reactive B cell receptor (BCR). More importantly, we show that forced allelic inclusion modifies B cell fate; low quantities of self-antigen induce the selection and accumulation of increased numbers of self-reactive B cells with decreased expression of antigen-specific BCRs. By directly measuring antigen binding by intact B cells, we show that the low amounts of self-antigen select self-reactive B cells with a lower association constant. A fraction of these B cells is activated and secretes autoantibodies that form circulating immune complexes with self-antigen. These findings demonstrate that conventional B cells can undergo positive selection and that the fate of a self-reactive B cell depends on the quantity of self-antigen, the number of BCRs engaged, and on its overall antigen-binding avidity, rather than on the affinity of individual BCRs.

B-cell homeostasis, competition, resources, and positive selection by self-antigens.

In adult mice, the number of B lymphocytes remains constant under homeostatic control, in spite of the fact that B cells are produced continuously in numbers that largely exceed the number required to replenish the peripheral pools. It follows that each newly formed lymphocyte can only persist if another lymphocyte dies. In an immune system where the total number of cells is limited, cell survival is no longer a passive phenomenon but rather a continuous active process where each lymphocyte must compete with other lymphocytes to survive. Consequently, the number and the life expectancy of a B-cell clone vary according to the presence or absence of competitor populations. This process of lymphocyte competition is likely controlled by a common need for resources that are in limited supply. The number of peripheral B-cells varies according to the availability of B-cell receptor (BCR) ligands. Indeed, it is possible to modify steady-state B-cell numbers by antigen manipulation. Moreover, conventional self-reactive B cells can undergo positive selection. We showed that the fate of a self-reactive B cell is determined by the quantity of self-antigens, the number of antigen-specific receptors engaged, and its overall antigen-binding avidity rather than the affinity of individual BCRs.