Apoptosis induced by the antigen receptor and Fas in a variant of the immature B cell line WEHI-231 and in splenic immature B cells

Signaling by the BCR causes proliferation and resistance to Fas-induced apo ptosis in mature B cells, but growth arrest and apoptosis in immature B cel ls. We have identified a variant of the immature a cell line WEHI 231 that retains the apoptotic response to the BCR but has acquired susceptibility t o Fas-induced apoptosis, The Fas susceptibility was associated with increas ed Fas expression on the cell surface and down-regulated IgD expression. Th ese cells exhibited a distinctive functional relationship in response to si gnals from the BCR, Fas and CD40: BCR stimulation markedly promoted Fas-med iated apoptosis land vice versa) and Fas-induced apoptosis was not subject to modulation by CD40 signaling. While BCR-induced apoptosis was effectivel y rescued by CD40, it was not affected by the expression of a dominant-nega tive FADD, The mechanistic distinctions between BCR- and Fas-induced apopto sis were further characterized by the differential effects of different cas pase inhibitors on these two processes which imply the involvement of diffe rent subsets of caspases, For BCR-induced apoptosis, we provide evidence th at the final apoptotic destruction phase can be inhibited by the pan-caspas e inhibitor BOC-Asp-FMK (BD) and that, in the presence of ED, the BCR only induces growth arrest which is reversible. The striking enhancing effects o f Fas on BCR-induced apoptosis seen in the variant cells prompted us to exa mine if a similar cooperation in induction of apoptosis occurs in the highl y tolerizable Immature B cells of the spleen. We found that the splenic imm ature a population contains a significant number of Fas-expressing cells, b ut neither Fas-induced apoptosis nor an enhancing effect of Fas on BCR-indu ced apoptosis of these cells was detected in vitro.