Campbell Family Institute, Ontario Cancer Institute, University of Toronto, Toronto, ON, Canada.
Eur J Immunol. 2010 Mar;40(3):867-77. doi: 10.1002/eji.200939445.
Elucidating the signaling events that promote T-cell tolerance versus activation provides important insights for manipulating immunity in vivo. Previous studies have suggested that the absence of PKCtheta results in the induction of anergy and that the balance between the induction of the transcription factors NFAT, AP1 and NF-kappaB plays a key role in determining whether T-cell anergy or activation is induced. Here, we examine whether Bcl-10 and specific family members of NF-kappaB act downstream of PKCtheta to alter CD8(+) T-cell activation and/or anergy. We showed that T cells from mice deficient in c-Rel but not NF-kappaB1 (p50) have increased susceptibility to the induction of anergy, similar to T cells from PKCtheta-deficient mice. Surprisingly T cells from Bcl-10-deficient mice showed a strikingly different phenotype to the PKCtheta-deficient T cells, with a severe block in TCR-mediated activation. Furthermore, we have also shown that survival signals downstream of NF-kappaB, are uncoupled from signals that mediate T-cell anergy. These results suggest that c-Rel plays a critical role downstream of PKCtheta in controlling CD8(+) T-cell anergy induction.
阐明促进 T 细胞耐受与激活的信号事件，为体内免疫调控提供了重要的见解。先前的研究表明，PKCθ 的缺失会导致无能的诱导，而转录因子 NFAT、AP1 和 NF-κB 的诱导平衡在决定 T 细胞无能或激活的诱导中起着关键作用。在这里，我们研究了 Bcl-10 和 NF-κB 的特定家族成员是否作为 PKCθ 的下游因子来改变 CD8(+)T 细胞的激活和/或无能。我们发现，缺乏 c-Rel 但不缺乏 NF-κB1（p50）的小鼠的 T 细胞对无能的诱导更容易产生易感性，类似于 PKCθ 缺陷型小鼠的 T 细胞。令人惊讶的是，Bcl-10 缺陷型小鼠的 T 细胞表现出与 PKCθ 缺陷型 T 细胞截然不同的表型，TCR 介导的激活严重受阻。此外，我们还表明，NF-κB 下游的存活信号与介导 T 细胞无能的信号脱耦。这些结果表明，c-Rel 在控制 CD8(+)T 细胞无能诱导中作为 PKCθ 的下游因子起着关键作用。
