Imbalanced signal transduction in FoxP3+ regulatory T cells
作者单位：Department of Immunology School of Basic Medical Sciences Fudan University Division of Immunology Department of Microbiology and Immunobiology Harvard Medical School
会议名称：《第十届全国免疫学学术大会》
会议日期：2015年
学科分类：1001[医学-基础医学(可授医学、理学学位)] 100102[医学-免疫学] 10[医学]
关 键 词：signal transduction regulatory T cells
摘 要：Regulatory T(Treg) cells characterized by the transcription factor FoxP3 have a fundamental role in the establishment and maintenance of peripheral tolerance, and have transcriptional and functional phenotypes that distinguish them from conventional CD4+ T cells(Tconv). There have been reports that these two CD4+ T cell subsets differ in the signaling downstream of T cell receptor-triggered activation, with different requirements for some signaling factors intermediates and lower responsiveness in Treg cells. Seeking a more comprehensive view, we found that Treg cells have a broadly dampened activation of several pathways and signaling nodes, with low phosphorylation of CD3ζ, SLP76, Erk1/2, AKT, or S6 and lower calcium influx, upon TCR-mediated activation. Examination of STAT responses to cytokines highlighted striking variations in Treg vs Tconv responses to interferons, IL2 or IL6, but no general Treg signaling defect. Treg/Tconv differences in responses were not due to different TCR levels, but much of the difference could be attributed to lower responsiveness of cells with a CD44 or CD62 L cells, which form a greater proportion of the Treg pool. Testing putative candidate regulators, the Treg/Tconv differential could not be explained by Treg over-expression of the signaling modulator CD5, the co-inhibitors PD- and CTLA4, or the regulatory phosphatase DUSP4. However, gene expression profiling in Dusp4-deficient mice showed that DUSP4 enhances the expression of a segment of the canonical Treg transcriptional signature, a module which overlaps in part with the TCR-dependent Treg gene set. Taken together, our findings show Treg cell signaling to be tuned down, plausibly because of their intrinsically higher reactivity to self, but comparatively more attuned to cytokines or other inter-cellular signals.