Regulation Of The Immune Response By The Inositol Phosphatase SHIP

在SHIP缺失的小鼠中观察到了淋巴细胞异常，但尚不清楚它们是由于这些细胞中SHIP的内在要求还是严重的髓系病理的结果。为了准确定位SHIP在T细胞中的功能，我们培育了T和B细胞特异性缺失SHIP的小鼠。具有SHIP T细胞特异性缺失的小鼠在明胶/NP-CGG免疫后表现出较差的抗体反应，并且当受到曼氏血吸虫卵攻击时，Th2细胞因子的产生减少。未能偏向Th2应答可能是Th1相关转录因子T-bet基础水平升高的结果，这是由于对细胞因子介导的T-bet诱导的敏感性增强所致。SHIP缺陷的CD8细胞表现出增强的细胞毒反应，这与这些细胞中T-bet水平的升高一致。总体而言，我们的实验表明，在T细胞中，SHIP以一种允许有效的Th2反应并限制T细胞细胞毒的方式负面调节细胞因子介导的激活。带有B细胞特异性SHIP缺失的小鼠我们已经确定SHIP-1通过调节转录因子T-bet和STAT1以及激活诱导的胞苷脱氨酶(AID)的表达，在类开关重组(CSR)中发挥B细胞内在的调节作用。

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).