Mature B-lymphocytes develop sequentially from transitional type 1 (T1) and type 2 (T2) precursors in the spleen. To elucidate the mechanisms that regulate the developmental fate of these distinct B cell subsets, we investigated their biochemical and biological responses following stimulation through the B-cell antigen receptor (BCR). As compared with the T1 subset, T2 cells are more responsive to BCR engagement, as evidenced by their robust induction of activation markers, expression of the prosurvival protein Bcl-x(L), and enhanced proliferation. BCR stimulation of T2 cells leads to the appearance of B cells with mature phenotypic characteristics, whereas T1 cells die. All of these T2 responses are dependent on the BCR signal transducer Bruton's tyrosine kinase, which is dispensable for the T1 to T2 transition. Furthermore, the serine/threonine kinases ERK, p38 MAPK, and Akt are predominantly activated in T2 compared with T1 B cells following BCR cross-linking. We conclude that T1 and T2 B cells respond differentially to BCR engagement via the induction of stage-specific signaling pathways. In turn, these signaling pathways probably govern the development and selection processes that are critical for the formation of the mature B cell compartment.
