Germinal centers regulate human Th2 development
Germinal centers regulate human Th2 development
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DOI：
10.4049/jimmunol.171.4.1657
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发表时间：
2003-08-15
影响因子：
4.4
通讯作者：
Borrebaeck, CAK
中科院分区：
文献类型：
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作者：
Johansson-Lindbom, B;Ingvarsson, S;Borrebaeck, CAK
在本研究中，我们证明人扁桃体中所有表达Th2选择性受体趋化受体同源分子（CRTH2）的人扁桃体CD4（+）T细胞也1）表达高水平的CXCR5，2）表现出过渡性CD45RA / RO表型，并且在立即离体分析时始终不产生大量细胞因子。因此，它们代表 Th2 效应细胞的前体，这一结论通过它们在体外激活后大量产生 IL-4、IL-5 和 IL-13 而不是 IYN-γ 得到证实。 CD4(+) T 细胞仅表达中等水平的 CXCR5，但在相同的培养条件下却发育为产生 IFN-γ 的细胞，从而在 CXCR5 表达的相对水平与获得的细胞因子谱之间建立了相关性。由于CXCR5在滤泡定位中发挥着至关重要的作用，因此结果表明这些CRTH2(+) Th2细胞优先在生发中心(GC)内发育其产生细胞因子的表型，而滤泡外分化反而促进Th1发育。为了支持这一提议，我们证明，如果与同种异体 GC B 细胞一起培养，具有 CXCR5 中间表达的 T 细胞也可以被迫产生 IL-4 和 IL-13。最后，我们证明之前描述的CD57(+) GC T细胞也表达高水平的CXCR5，但它们不包含Th2前体，而是代表失能的T细胞。总而言之，这些数据表明，GC 和 B 细胞以精细调节的方式调节 CD4+ T 细胞的分化，要么通过促进 Th2 细胞的分化（Th2 细胞在进化出产生细胞因子的表型之前明显离开淋巴组织），要么通过使 T 细胞无反应。
In the present study we demonstrate that all CD4(+) T cells in human tonsil expressing the Th2-selective receptor chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) also 1) express high levels of CXCR5, and 2) display a transitional CD45RA/RO phenotype and consistently do not produce significant amounts of cytokines when immediately analyzed ex vivo. Hence, they represent precursors of Th2 effector cells, a conclusion confirmed by their robust production of IL-4, IL-5, and IL-13, but not IYN-gamma, after in vitro activation. CD4(+) T cells, which express only intermediate levels of CXCR5, instead develop into IFN-gamma-producing cells under identical culture conditions, thus establishing a correlation between relative levels of CXCR5 expression and the acquired cytokine profile. Because CXCR5 is critically involved in follicular localization, the results suggest that these CRTH2(+) Th2 cells preferentially develop their cytokine-producing phenotype within germinal centers (GCs), whereas extrafollicular differentiation instead promotes Th1 development. In support for this proposal, we show that T cells with an intermediate expression of CXCR5 can be forced to also produce IL-4 and IL-13 if cultured with allogenic GC B cells. Finally, we demonstrate that the previously described CD57(+) GC T cells also express high levels of CXCR5 but instead of comprising a Th2 precursor, they represent anergized T cells. Taken together, these data suggest that GCs and B cells regulate CD4(+) T cell differentiation in a finely tuned fashion, either by promoting differentiation of Th2 cells, which apparently leave the lymphoid tissue before evolving a cytokine-producing phenotype, or by furnishing T cell unresponsiveness.