Lymphocyte anomalies have been observed in SHIP-null mice but it is unclear whether they are due to an intrinsic requirement of SHIP in these cells or a consequence of the severe myeloid pathology. To precisely address the function of SHIP in T cells we have generated mice with T and B cell-specific deletion of SHIP. Mice with T cell-specific deletion of SHIP show poor antibody responses upon Alum/NP-CGG immunization and diminished Th2 cytokine production when challenged with Schistosoma mansoni eggs. The failure to skew to Th2 responses may be the consequence of increased basal levels of the Th1-associated transcriptional factor T-bet, resulting from enhanced sensitivity to cytokine-mediated T-bet induction. SHIP-deficient CD8+ cells show enhanced cytotoxic responses, consistent with elevated T-bet levels in these cells. Overall our experiments indicate that in T cells, SHIP negatively regulates cytokine-mediated activation in a way that allows effective Th2 responses and limits T cell cytotoxicity. Mice with B cell-specific deletion of SHIP We have determined that SHIP-1 plays a B cell-intrinsic regulatory role in class switch recombination (CSR) by modulating the expression of the transcription factors: T-bet and STAT1 and the enzyme, activation induced cytidine deaminase (AID).
