Hu Jianfang, August Avery
Center for Molecular Immunology and Infectious Disease and Department of Veterinary & Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802, USA.
J Immunol. 2008 May 15;180(10):6544-52. doi: 10.4049/jimmunol.180.10.6544.
The Tec family kinase Itk regulates the development of conventional and innate CD8(+) T cells. However, little is known about the role of Itk in the development of CD4(+) T cell lineages, although the role of Itk in the T cell activation and function is well defined. We show in this study that Itk null mice have increased percentage of CD62L(low)CD44(high) memory phenotype CD4(+) T cells compared with wild-type mice. These cells arise directly in the thymus, express high levels of transcripts for the T-bet and IFN-gamma and are able to produce IFN-gamma directly ex vivo in response to stimulation. Itk deficiency greatly decreases the number of CD4(+) T cells with CD62L(high)CD44(low) naive phenotype, but has no effect on the number of memory phenotype CD4(+) T cells, indicating that the development of memory phenotype CD4(+) T cells is Itk-independent. We further show that the development of the naive phenotype CD4(+) T cells is dependent on active Itk signals and can be rescued by expression of Itk specifically in T cells. Our data also show that Itk is required for functional TCR signaling in these cells, but not for the innate function in response to IL-12/IL-18 or Listeria monocytogenes stimulation. These results indicate that CD62L(high)CD44(low) "naive" CD4(+) and CD62L(low)CD44(high) "innate memory phenotype" CD4(+) T cells may be independent populations that differ in their requirement for Itk signals for development. Our data also suggest that CD4(+)CD62L(low)CD44(high) memory phenotype T cells have innate immune function.
Tec家族激酶Itk调节传统型和天然CD8(+) T细胞的发育。然而，尽管Itk在T细胞活化和功能方面的作用已明确，但对于Itk在CD4(+) T细胞谱系发育中的作用却知之甚少。我们在本研究中表明，与野生型小鼠相比，Itk基因敲除小鼠中CD62L(low)CD44(high)记忆表型CD4(+) T细胞的百分比增加。这些细胞直接在胸腺中产生，表达高水平的T-bet和IFN-γ转录本，并且能够在体外受到刺激时直接产生IFN-γ。Itk缺陷极大地减少了具有CD62L(high)CD44(low)幼稚表型的CD4(+) T细胞数量，但对记忆表型CD4(+) T细胞数量没有影响，这表明记忆表型CD4(+) T细胞的发育不依赖于Itk。我们进一步表明，幼稚表型CD4(+) T细胞的发育依赖于活跃的Itk信号，并且可以通过在T细胞中特异性表达Itk来挽救。我们的数据还表明，Itk是这些细胞中功能性TCR信号传导所必需的，但对于响应IL-12/IL-18或单核细胞增生李斯特菌刺激的天然功能则不是必需的。这些结果表明，CD62L(high)CD44(low) “幼稚” CD4(+)和CD62L(low)CD44(high) “天然记忆表型 ” CD4(+) T细胞可能是独立的群体，它们在发育对Itk信号的需求上有所不同。我们的数据还表明，CD4(+)CD62L(low)CD44(high)记忆表型T细胞具有天然免疫功能。
