A Th17-like developmental process leads to CD8+ Tc17 cells with reduced cytotoxic activity
A Th17-like developmental process leads to CD8+ Tc17 cells with reduced cytotoxic activity
复制标题
DOI：
10.1002/eji.200939412
复制
发表时间：
2009-07-01
影响因子：
5.4
通讯作者：
Lohoff, Michael
中科院分区：
文献类型：
--
作者：
Huber, Magdalena;Heink, Sylvia;Lohoff, Michael
在不存在偏斜细胞因子的情况下，用抗原激活初始CD 8（+）T细胞触发其分化为效应CTL，其诱导靶细胞死亡。我们发现，在细胞因子IL-6或IL-21加TGF-β存在下活化的CD 8（+）T细胞与CD 4（+）T细胞相似，发育成产生IL-17（Tc 17）的细胞。这些细胞显示出沿着低水平的CTL标志物的极大抑制的细胞毒性功能：T盒转录因子Eomesodermin、颗粒酶B和IFN-γ。相反，这些细胞表达Th 17程序的标志分子，包括视黄酸受体相关孤儿受体（ROR）γ t、ROR α、IL-21和IL-23 R。17型主调节因子ROR γ t的表达与Tc 17的产生有因果关系，因为其过表达在IL-6或IL-21存在下刺激IL-17的产生。17型程序的上调以及CTL分化的抑制都是STAT 3依赖性的。此外，在多发性硬化症的小鼠模型EAE中也可检测到产生IL-17但不产生颗粒酶B的Tc 17细胞。我们的数据表明，在体外和体内存在相互排斥的CTL和Tc 17发育途径。
Activation of naive CD8(+) T cells with antigen in the absence of skewing cytokines triggers their differentiation into effector CTL, which induces death of target cells. We show that CD8(+) T cells activated in the presence of the cytokines IL-6 or IL-21 plus TGF-beta similar to CD4(+) T cells, develop into IL-17-producing (Tc17) cells. These cells display greatly suppressed cytotoxic function along with low levels of the CTL markers: T-box transcription factor Eomesodermin, granzyme B and IFN-gamma. Instead, these cells express hallmark molecules of Th17 program including retinoic acid receptor-related orphan receptor (ROR)gamma t, ROR alpha, IL-21 and IL-23R. The expression of the type 17 master regulator ROR gamma t is causally linked to Tc17 generation, because its overexpression stimulates production of IL-17 in the presence of IL-6 or IL-21. Both, upregulation of the type 17 program as well as suppression of CTL differentiation are STAT3 dependent. Furthermore, Tc17 cells producing IL-17 but not granzyme B are also detectable in EAE, a mouse model for multiple sclerosis. Our data point to the existence of mutually exclusive CTL and Tc17 developmental pathways in vitro and in vivo.