Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine Sendai, Japan.
Front Immunol. 2012 May 28;3:133. doi: 10.3389/fimmu.2012.00133. eCollection 2012.
Antigen primed T lymphocytes need to expand and persist to promote adaptive immunity. The growth and survival signals that control this are in large part provided by the NF-κB pathway in activated or effector/memory T cells. Although several membrane receptors impact NF-κB activation, signaling from OX40 (CD134, TNFRSF4), a member of the tumor necrosis factor receptor (TNFR) superfamily, has proven to be important for T cell immunity and a strong contributor to NF-κB activity. PKCθ directs the T cell receptor (TCR) and CD28-dependent assembly of a CBM complex (CARMA1, BCL10, and MALT1) for efficient activation of NF-κB, raising the question of whether other membrane bound receptors that activate NF-κB also require this PKCθ-CBM axis to control TCR-independent T cell activity. We discuss here our recent data demonstrating that after ligation by OX40L (CD252, TNFSF4) expressed on antigen-presenting cells, OX40 translocates into detergent-insoluble membrane lipid microdomains (DIM or lipid rafts) in T cells irrespective of TCR signals, and assembles into a signaling complex containing PKCθ, together with TRAF2, RIP1, the CBM complex, and the IKKα/β/Γ complex. PKCθ is required for optimal NF-κB activation mediated by OX40 and thus works as an essential component of this OX40 signalosome. We also discuss the likelihood that other TNFR superfamily molecules might complex with PKCθ in T cells, and whether PKC isoforms may be critical to the function of TNFR molecules in general.
抗原致敏的 T 淋巴细胞需要扩增和持续存在以促进适应性免疫。控制这一过程的生长和存活信号在很大程度上是由激活或效应/记忆 T 细胞中的 NF-κB 途径提供的。尽管有几种膜受体影响 NF-κB 的激活，但 OX40（CD134，TNFRSF4）的信号，肿瘤坏死因子受体（TNFR）超家族的成员，已被证明对 T 细胞免疫很重要，并且是 NF-κB 活性的重要贡献者。PKCθ 指导 TCR 和 CD28 依赖性 CBM 复合物（CARMA1、BCL10 和 MALT1）的组装，以有效激活 NF-κB，这引发了一个问题，即其他激活 NF-κB 的膜结合受体是否也需要这种 PKCθ-CBM 轴来控制 TCR 非依赖性 T 细胞活性。我们在这里讨论了我们最近的数据，这些数据表明，在抗原呈递细胞上表达的 OX40L（CD252，TNFSF4）与 OX40 结合后，OX40 会转位到 T 细胞中的去污剂不可溶膜脂微区（DIM 或脂筏）中，而与 TCR 信号无关，并与 PKCθ 一起组装成信号复合物，该复合物包含 TRAF2、RIP1、CBM 复合物和 IKKα/β/Γ 复合物。PKCθ 是 OX40 介导的最佳 NF-κB 激活所必需的，因此是 OX40 信号体的必需组成部分。我们还讨论了其他 TNFR 超家族分子是否可能与 T 细胞中的 PKCθ 形成复合物的可能性，以及 PKC 同工型是否可能对 TNFR 分子的一般功能至关重要。
