Single cell analysis reveals regulated hierarchical T cell antigen receptor signaling thresholds and intraclonal heterogeneity for individual cytokine responses of CD4+ T cells.
Single cell analysis reveals regulated hierarchical T cell antigen receptor signaling thresholds and intraclonal heterogeneity for individual cytokine responses of CD4+ T cells.
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DOI：
10.1084/jem.186.5.757
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发表时间：
1997-08-29
期刊：
影响因子：
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通讯作者：
Germain RN
中科院分区：
文献类型：
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作者：
Itoh Y;Germain RN
肽-主要组织相容性复合物抗原的T细胞受体（TCR）识别可以引起多种效应物活性。在这里，我们同时分析TCR的参与和生产的多种细胞因子的单个细胞在一个克隆的Th 1 CD 4+细胞群体。低浓度的TCR配体仅引起干扰素-γ（IFN-γ）产生。增加配体募集更多的细胞进入IFN-γ+池，增加每个细胞产生的IFN-γ，并且还增加IL-2，但仅来自已经产生IFN-γ的细胞。大多数仅产生IFN-γ的细胞显示出比产生两种细胞因子的细胞更少的TCR下调，这与引发IL-2而不是诱发IFN-γ合成需要更多TCR信号传导一致。这些研究强调了TCR信号传导阈值的分级组织，用于诱导不同的细胞因子应答，并证明这种阈值现象适用于单个细胞。此类阈值的存在表明，抗原剂量通过改变活化T细胞产生的细胞因子的比例，不仅可以决定免疫反应的程度，还可以决定免疫反应的质量。在这个反应层次的定量关系的变化，通过CD 28或LFA-1的共刺激，以及淋巴细胞的分化状态，解释如何在面对一个固定的抗原负荷，这些参数的变化可以定性地影响免疫结果。最后，尽管在大多数细胞中观察到IFN-γ/IL-2等级，但在具有最大TCR下调的细胞中，一些细胞仅产生IFN-γ而不产生IL-2，并且IFN-γ的量超过双产生者中的量。因此，这些单细胞分析也提供了明确的证据，非定量的细胞因子产生的长期Th 1细胞的克隆内异质性，表明额外的复杂性T细胞功能在免疫反应。
T cell receptor (TCR) recognition of peptide–major histocompatibility complex antigens can elicit a diverse array of effector activities. Here we simultaneously analyze TCR engagement and the production of multiple cytokines by individual cells in a clonal Th1 CD4+ cell population. Low concentrations of TCR ligand elicit only interferon-γ (IFN-γ) production. Increasing ligand recruits more cells into the IFN-γ+ pool, increases IFN-γ produced per cell, and also elicits IL-2, but only from cells already making IFN-γ. Most cells producing only IFN-γ show less TCR downmodulation than cells producing both cytokines, consistent with a requirement for more TCR signaling to elicit IL-2 than to evoke IFN-γ synthesis. These studies emphasize the hierarchical organization of TCR signaling thresholds for induction of distinct cytokine responses, and demonstrate that this threshold phenomenon applies to individual cells. The existence of such thresholds suggests that antigen dose may dictate not only the extent, but also the quality of an immune response, by altering the ratios of the cytokines produced by activated T cells. The quantitative relationships in this response hierarchy change in response to costimulation through CD28 or LFA-1, as well as the differentiation state of the lymphocyte, explaining how variations in these parameters in the face of a fixed antigen load can qualitatively influence immune outcomes. Finally, although the IFN-γ/IL-2 hierarchy is seen with most cells, among cells with the greatest TCR downmodulation, some produce only IFN-γ and not IL-2, and the amount of IFN-γ exceeds that in double producers. Thus, these single cell analyses also provide clear evidence of nonquantitative intraclonal heterogeneity in cytokine production by long-term Th1 cells, indicating additional complexity of T cell function during immune responses.