Casey Kerry A, Mescher Matthew F
Center for Immunology, Department of Laboratory Medicine and Pathology, University of Minnesota, 420 Delaware Street SE, Minneapolis, MN 55455, USA.
J Immunol. 2007 Jun 15;178(12):7640-8. doi: 10.4049/jimmunol.178.12.7640.
IL-21, the most recently described member of the common gamma-chain cytokine family, is produced by activated CD4 T cells, whereas CD8 T cells express the IL-21 receptor. To investigate a possible role for IL-21 in the priming of naive CD8 T cells, we examined responses of highly purified naive OT-I CD8 T cells to artificial APCs displaying Ag and B7-1 on their surface. We found that IL-21 enhanced OT-I clonal expansion and supported development of cytotoxic effector function. High levels of IL-2 did not support development of effector functions, but IL-2 was required for optimal responses in the presence of IL-21. IL-12 and IFN-alpha have previously been shown to support naive CD8 T cell differentiation and acquisition of effector functions through a STAT4-dependent mechanism. Here, we show that IL-21 does not require STAT4 to stimulate development of cytolytic activity. Furthermore, IL-21 fails to induce IFN-gamma or IL-4 production and can partially block IL-12 induction of IFN-gamma production. CD8 T cells that differentiate in response to IL-21 have a distinct surface marker expression pattern and are characterized as CD44(high), PD-1(low), CD25(low), CD134(low), and CD137(low). Thus, IL-21 can provide a signal required by naive CD8 T cells to differentiate in response to Ag and costimulation, and the resulting effector cells represent a unique effector phenotype with highly effective cytolytic activity, but deficient capacity to secrete IFN-gamma.
白细胞介素-21（IL-21）是γ链共细胞因子家族中最新发现的成员，由活化的CD4 T细胞产生，而CD8 T细胞表达IL-21受体。为了研究IL-21在初始CD8 T细胞致敏过程中可能发挥的作用，我们检测了高度纯化的初始OT-I CD8 T细胞对表面展示抗原（Ag）和B7-1的人工抗原呈递细胞（APC）的反应。我们发现，IL-21增强了OT-I克隆扩增，并促进了细胞毒性效应功能的发育。高水平的IL-2不能促进效应功能的发育，但在有IL-21存在的情况下，IL-2是最佳反应所必需的。此前已表明，IL-12和干扰素-α（IFN-α）通过依赖信号转导和转录激活因子4（STAT4）的机制支持初始CD8 T细胞分化并获得效应功能。在此，我们表明，IL-21刺激溶细胞活性的发育不需要STAT4。此外，IL-21不能诱导干扰素-γ（IFN-γ）或白细胞介素-4（IL-4）的产生，并且可以部分阻断IL-12诱导的IFN-γ产生。响应IL-21而分化的CD8 T细胞具有独特的表面标志物表达模式，其特征为CD44（高）、程序性死亡蛋白1（PD-1）（低）、CD25（低）、CD134（低）和CD137（低）。因此，IL-21可以提供初始CD8 T细胞响应抗原和共刺激而分化所需的信号，并且产生的效应细胞代表一种独特的效应细胞表型，具有高效的溶细胞活性，但分泌IFN-γ的能力不足。
