IL-4 directs the development of Th2-like helper effectors.
IL-4 directs the development of Th2-like helper effectors.
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DOI：
10.4049/jimmunol.145.11.3796
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发表时间：
1990-12
影响因子：
4.4
通讯作者：
S. Swain;A. Weinberg;M. English;G. Huston
中科院分区：
文献类型：
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作者：
S. Swain;A. Weinberg;M. English;G. Huston
我们的研究表明，在初始Th细胞应答过程中白细胞介素 - 4（IL - 4）的存在会使前体细胞发育成一个主要由“类Th2”效应细胞组成的群体，这些效应细胞分泌IL - 4和IL - 5，但很少分泌IL - 2或干扰素 - γ（IFN - γ）。我们发现IL - 4和IL - 2的水平既决定了对有丝分裂原或抗原产生应答的效应细胞的水平，也决定了它们在再次刺激时所分泌的淋巴因子的模式。IL - 2是效应细胞最佳生成所必需的，并且IL - 2水平的升高会增加分泌IL - 4/IL - 5和IFN - γ的效应细胞的扩增。相比之下，IL - 4是分泌IL - 4/IL - 5的效应细胞发育所必需的，但会抑制IL - 2的产生，并且在较高剂量下会抑制4天后检测到的分泌IFN - γ的效应细胞的发育。在额外的1到2周后评估IL - 4存在与否的影响也很显著。当在第4天到第11天仅在IL - 2中培养有或没有初始IL - 4的培养物时，它们保持其独特的淋巴因子产生模式。在没有IL - 4的培养物中发育的那些细胞逐渐分泌更多的IL - 2，并且可以在IL - 2中维持和扩增。它们继续产生IFN - γ，尽管水平随时间有所下降，但它们不会获得产生IL - 4或IL - 5的能力。因此，这些细胞越来越类似于Th1细胞系。相反，在最初暴露于IL - 4的培养物中的那些细胞，在第4到第5天会产生分泌高水平IL - 4/IL - 5（加上不同水平的IFN - γ）的效应细胞，但所发育的细胞群体仅在IL - 2中不能很好地维持。那些存活下来的细胞继续分泌IL - 4和IL - 5，但不分泌IL - 2。此外，如果存在干扰素 - γ的产生，其会随时间下降。因此，这些培养物中的细胞呈现出越来越像Th2的表型。似乎低水平的IL - 4在第4天效应细胞中抑制IL - 2产生的作用似乎是暂时的，而较高水平的IL - 4似乎会驱动沿着一种独特的、不可逆的途径发育。这些研究支持这样一种概念，即辅助细胞的不同亚群（大致对应于Th1和Th2亚群）可以在短期培养中分别在低水平和高水平的IL - 4下快速发育。它们支持这样一种概念，即这种不同的表型来自不同的分化途径，这有望反映动物体内辅助性T细胞分化的途径。
Our studies show that the presence of IL-4 during the response of naive Th cells causes precursors to develop into a population comprised largely of "Th2-like" effectors that secrete IL-4 and IL-5, but little IL-2 or IFN-gamma. We find that the levels of IL-4 and IL-2 determine both the level of effectors developed in response to mitogen or Ag and the patterns of lymphokines they secrete when restimulated. IL-2 is required for optimum generation of effectors, and increasing levels of IL-2, augments the expansion of effectors secreting both IL-4/IL-5 and IFN-gamma. In contrast, IL-4 is required for the development of IL-4/IL-5 secreting effectors but suppresses the development of IL-2 and at higher doses IFN-gamma-secreting effectors detected after 4 days. Also dramatic are the effects of the presence or absence of IL-4 evaluated after an additional 1 to 2 wk. When cultures with or without initial IL-4 are cultured in IL-2 alone from days 4 to 11, they retain their distinct patterns of lymphokine production. Those cells that developed in cultures without IL-4 progressively secrete more IL-2 and can be maintained and expanded in IL-2. They continue to produce IFN-gamma, though the levels decrease somewhat with time, but they do not acquire the ability to produce IL-4 or IL-5. These cells thus increasingly resemble Th1 cell lines. In contrast, those cells in cultures initially exposed to IL-4, generate effectors which secrete high levels of IL-4/IL-5 (plus variable levels of IFN-gamma) at days 4 to 5, but the populations of cells developed, are not maintained well on IL-2 alone. Those cells that do survive continue to secrete IL-4 and IL-5 but not IL-2. In addition, IFN-gamma production, if present, falls off with time. Thus the cells in these cultures take on an increasingly Th2-like phenotype. It appears that the effects of low levels of IL-4 in suppressing IL-2 production by day 4 effectors appear to be transient whereas the higher levels appear to drive the development along a distinct pathway which is irreversible. These studies support the concept that different subsets of helper cells, which correspond roughly to Th1 and Th2 subsets, can develop rapidly in short term culture with respectively low vs high levels of IL-4. They support the concept that such distinct phenotypes arise from alternate pathways of differentiation that can be expected to reflect pathways available for helper T cell differentiation in the animal.