Role of Syk in B-cell development and antigen-receptor signaling

Antigen receptors (BCRs) on developing B lymphocytes play two opposing role s-promoting survival of cells that may later bind a foreign antigen and inh ibiting survival of cells that bind too strongly to self-antigens. It is no t known how these opposing outcomes are signaled by BCRs on immature B cell s. Here we analyze the effect of a null mutation in the Syk tyrosine kinase on maturing B cells displaying a transgene-encoded BCR that binds hen egg lysozyme (HEL). In the absence of HEL antigen, MEL-specific BCRs are expres sed normally on the surface of Syk-deficient immature B-lineage cells, but this fails to promote maturation beyond the earliest stages of B-lineage co mmitment. Binding of HEL antigen, nevertheless, triggers phosphorylation of CD79 alpha/beta BCR subunits and modulation of receptors from the surface in Syk-deficient cells, but it cannot induce an intracellular calcium respo nse. Continuous binding of low- or high-avidity forms of HEL, expressed as self-antigens, fails to restore the signal needed for maturation. Compared with the effects in the same system of null mutations in other BCR signalin g elements, such as CD45 and Lyn kinase, these results indicate that Syk is essential for transmitting a signal that initiates the program of B-lympho cyte maturation.