Human memory B cells that carry mutated IgV region genes were isolated from tonsils by negative selection of IgD+ naive B cells and CD38+ germinal center B cells and plasma cells. They were mainly found within the intraepithelial areas, but not in the B cell follicles of human tonsils. Memory B cells but not naive B cells have the capacity to present antigen directly to T cells, owing to the constitutive expression of the accessory molecules B7-1/CD80 and B7-2/CD86. Signals through antigen receptors and CD40 antigen result in these two molecules being further up-regulated more rapidly and strongly on memory B cells than on naive B cells. The unique anatomical localization of memory B cells beneath the surface of mucosa, together with their strong APC capacity, may explain the well-known prompt and robust secondary antibody responses.

SummaryThe antigen receptors on T and B lymphocytes can transduce both agonist and antagonist signals leading either to activation/survival or anergy/death. The outcome of B lymphocyte antigen receptor (BCk) triggering depends upon multiple parameters which include (a) antigen concentration and valency, (b) duration of BCP,. occupancy, (c) receptor affinity, and (d) B cell differentiation stages. Herein, using anti-immunoglobulin K and k light chain antibodies, we analyzed the response of human naive, germinal center (GC) or memory B cells to BCR crosslinking regardless of heavy chain Ig isotype or intrinsic BCR specificity. We show that after CD40-activation, anti-BCR.(K+k) can elicit an intracellular calcium flux on both GC and non-GC cells. However, prolonged BCP, cross-linking induces death of CD40-activated GC B cells but enhances proliferation of naive or memory cells. Anti-K antibody only kills K + GC B cells without affecting surrounding k + GC B cells, thus demonstrating that BCR-mediated killing of GC B lymphocytes is a direct effect that does not involve a paracrine mechanism. BCR-mediated killing of CD40-activated GC B cells could be partially antagonized by the addition of IL-4. Moreover, in the presence of IL-4, prestimulation through CD40 could prevent subsequent anti-Ig-mediated cell death, suggesting a specific role of this combination in selection of GC B cells. This report provides evidence that in human, susceptibility to BCP, killing is regulated along peripheral B cell differentiation pathway.

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