Pinpointing IL-4-independent acquisition and IL-4-influenced maintenance of Th2 activity by CD4 T cells
Pinpointing IL-4-independent acquisition and IL-4-influenced maintenance of Th2 activity by CD4 T cells
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DOI：
10.1002/eji.200324510
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发表时间：
2004-03-01
影响因子：
5.4
通讯作者：
MacLennan, ICM
中科院分区：
文献类型：
--
作者：
Cunningham, AF;Serre, K;MacLennan, ICM
初始CD 4 T细胞通过产生IL-4 mRNA并诱导B细胞产生γ 1和γ-开关转录物，在对明矾沉淀蛋白的初级应答早期产生Th 2活性。IL-4诱导的IL-4依赖性和IL-4非依赖性途径都得到了认可，但它们对体内初级Th 2应答不同阶段的相对贡献尚不确定。我们发现，淋巴结中对铝沉淀蛋白的IL-4合成的主要诱导绝大多数是在抗原特异性CD 4 T细胞中，并且在IL-4 R α（-/-）小鼠中未受损，其可以产生但不响应IL-4和IL-13。在这些小鼠中，反映Th 2活性的卵泡外反应中的IG类别转换也未受损。相比之下，免疫后7天-当T细胞选择生发中心的B细胞并且T细胞引发已经发生时-对IL-4的无应答性与较小的生发中心、增加的T-bet和γ 2a开关转录物水平以及减少的γ 1和γ 2 α转录物相关。这些数据表明，在T细胞引发过程中获得的Th 2特性和初始的CD 4 T细胞与B细胞的相互作用在很大程度上是IL-4非依赖性的，而在引发过程中诱导的IL-4产生在维持Th 2表型中具有重要作用，因为T细胞在生殖中心选择B细胞。
Naive CD4 T cells develop Th2 activity early in primary responses to alum-precipitated proteins by producing IL-4 mRNA and inducing B cells to produce gamma1 and epsilon switch transcripts. Both IL-4-dependent and IL-4-independent pathways for IL-4 induction are recognized, but their relative contribution to the different phases of primary Th2 responses in vivo is uncertain. We show the primary induction of IL-4 synthesis in lymph nodes responding to alumprecipitated protein is overwhelmingly in antigen-specific CD4 T cells and is unimpaired in IL-4Ralpha(-/-) mice, which can produce but do not respond to IL-4 and IL-13. Ig class-switching in extra-follicular responses, reflecting Th2 activity, is also unimpaired in these mice. By contrast, 7 days after immunization - when T cells are selecting B cells in germinal centers and T cell priming has occurred - non-responsiveness to IL-4 is associated with smaller germinal centers, increased levels of T-bet and gamma2a switch transcripts and reduced gamma1 and epsilon transcripts. These data indicate that Th2 characteristics acquired during T cell priming and the initial CD4 T cell interaction with B cells are largely IL-4-independent, whereas IL-4 production induced during priming has a significant role in maintaining the Th2 phenotype as T cells select B cells in germinal centers.