In APCs, the protein tyrosine kinase Syk is required for signaling of several 
immunoreceptors, including the BCR and FcR. We show that conditional ablation of 
the syk gene in dendritic cells (DCs) abrogates FcgammaR-mediated cross priming 
of diabetogenic T cells in RIP-mOVA mice, a situation phenocopied in wild-type 
RIP-mOVA mice treated with the selective Syk inhibitor R788. In addition to 
blocking FcgammaR-mediated events, R788 also blocked BCR-mediated Ag 
presentation, thus broadly interrupting the humoral contributions to T 
cell-driven autoimmunity. Indeed, oral administration of R788 significantly 
delayed spontaneous diabetes onset in NOD mice and successfully delayed 
progression of early-established diabetes even when treatment was initiated 
after the development of glucose intolerance. At the DC level, R788 treatment 
was associated with reduced insulin-specific CD8 priming and decreased DC 
numbers. At the B cell level, R788 reduced total B cell numbers and total Ig 
concentrations. Interestingly, R788 increased the number of IL-10-producing B 
cells, thus inducing a tolerogenic B cell population with immunomodulatory 
activity. Taken together, we show by genetic and pharmacologic approaches that 
Syk in APCs is an attractive target in T cell-mediated autoimmune diseases such 
as type 1 diabetes.