Miller Andrew T, Wilcox Heather M, Lai Zhongbin, Berg Leslie J
Department of Pathology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester 01655, USA.
Immunity. 2004 Jul;21(1):67-80. doi: 10.1016/j.immuni.2004.06.009.
The Tec family tyrosine kinase, Itk, is critical for PLC-gamma1 activation downstream of the TCR. Studies of Itk-/- mice have demonstrated a requirement for Itk in Th2 cytokine production and protective immunity to parasitic infections. Here we address the mechanism by which Itk regulates Th2 differentiation. We find that naive Itk-/- CD4+ T cells respond normally to cytokine skewing signals and can differentiate efficiently into either Th1 or Th2 lineage cells. In the absence of skewing cytokines, wild-type CD4+ T cells stimulated with low-avidity ligands preferentially express GATA-3 mRNA and differentiate into Th2 cells. Under these same stimulation conditions, Itk-/- T cells produce large amounts of T-bet mRNA and differentiate into IFN-gamma-producing cells. Furthermore, Itk is upregulated during Th2 differentiation, while Rlk, a related Tec kinase, disappears rapidly from differentiating Th2 cells. Together, these findings provide a molecular explanation for the essential role of Itk in Th2 differentiation.
Tec家族酪氨酸激酶Itk对于TCR下游的PLC-γ1激活至关重要。对Itk基因敲除小鼠的研究表明，Itk对于Th2细胞因子的产生以及对寄生虫感染的保护性免疫是必需的。在此，我们探讨Itk调节Th2分化的机制。我们发现，未经刺激的Itk基因敲除CD4⁺ T细胞对细胞因子偏向信号反应正常，并且能够有效地分化为Th1或Th2谱系细胞。在没有偏向性细胞因子的情况下，用低亲和力配体刺激的野生型CD4⁺ T细胞优先表达GATA-3 mRNA并分化为Th2细胞。在相同的刺激条件下，Itk基因敲除T细胞产生大量的T-bet mRNA并分化为产生IFN-γ的细胞。此外，在Th2分化过程中Itk表达上调，而相关的Tec激酶Rlk在分化的Th2细胞中迅速消失。这些发现共同为Itk在Th2分化中的重要作用提供了分子解释。
