BCL-2 ALTERS THE ANTIGEN-DRIVEN SELECTION OF B-CELLS IN MU-KAPPA BUT NOT IN MU-ONLY XID TRANSGENIC MICE

A point mutation in the pleckstrin homology domain of the mouse Bruton 's tyrosine kinase (btk) gene results in an X-linked immune defect, Xi d, characterized by immunologic unresponsiveness to polymeric carbohyd rate Ags. In Xid mice, B cells specific for phosphocholine (PC) do not develop in peripheral lymphoid tissues because they either fail to be positively selected from the marrow or they are clonally deleted via an Ag-driven, receptor-mediated process, Overexpression of the bd-2 ge ne allows PC-specific B cells to survive and mature in Xid mu kappa an ti-PC transgenic mice, but PC-specific B cells are not rescued by bd-2 in Xid mu-only transgenic mice. The failure of bd-2 to rescue PC-spec ific B cells in mu-only transgenic mice suggests that either it does n ot correct the btk defect in the Ag-driven selection process that occu rs in pre-B cells and/or in very immature B cells or that a btk-depend ent proliferative phase is required for the selection and amplificatio n of the PC-specific B cells in mu-only transgenic mice. The rescue of PC-specific B cells in mu kappa transgenic mice indicates that bd-2 c an alter receptor-mediated B cell selection at late stages in B cell d evelopment, The rescued PC-specific B cells in Xid male mice do not ex hibit an altered proliferation profile in response to B cell-stimulati ng agents compared with B cells from unmanipulated Xid mice; thus, the y fail to respond to soluble anti-mu or PC-dextran hut they proliferat e in response to PC, anti-mu, or anti-ld conjugated to Sepharose.