Department of Cell and Developmental Biology, School of Biological Sciences, University of California San Diego, La Jolla, CA 92093, USA.
Department of Pathology, University of California San Diego, La Jolla, CA 92093, USA.
Immunity. 2023 Jun 13;56(6):1187-1203.e12. doi: 10.1016/j.immuni.2023.04.005. Epub 2023 May 8.
B7 ligands (CD80 and CD86), expressed by professional antigen-presenting cells (APCs), activate the main co-stimulatory receptor CD28 on T cells in trans. However, in peripheral tissues, APCs expressing B7 ligands are relatively scarce. This raises the questions of whether and how CD28 co-stimulation occurs in peripheral tissues. Here, we report that CD8 T cells displayed B7 ligands that interacted with CD28 in cis at membrane invaginations of the immunological synapse as a result of membrane remodeling driven by phosphoinositide-3-kinase (PI3K) and sorting-nexin-9 (SNX9). cis-B7:CD28 interactions triggered CD28 signaling through protein kinase C theta (PKCθ) and promoted CD8 T cell survival, migration, and cytokine production. In mouse tumor models, loss of T cell-intrinsic cis-B7:CD28 interactions decreased intratumoral T cells and accelerated tumor growth. Thus, B7 ligands on CD8 T cells can evoke cell-autonomous CD28 co-stimulation in cis in peripheral tissues, suggesting cis-signaling as a general mechanism for boosting T cell functionality.
B7 配体（CD80 和 CD86）由专业抗原呈递细胞（APC）表达，在转导中激活 T 细胞上的主要共刺激受体 CD28。然而，在外周组织中，表达 B7 配体的 APC 相对较少。这就提出了一个问题，即在周围组织中是否以及如何发生 CD28 共刺激。在这里，我们报告说，CD8 T 细胞在免疫突触的膜凹陷处显示出 B7 配体，这些配体通过由磷酸肌醇 3-激酶（PI3K）和分选连接蛋白 9（SNX9）驱动的膜重塑，与 CD28 在顺式相互作用。顺式-B7:CD28 相互作用通过蛋白激酶 C θ（PKCθ）触发 CD28 信号转导，并促进 CD8 T 细胞的存活、迁移和细胞因子产生。在小鼠肿瘤模型中，缺失 T 细胞内在的顺式-B7:CD28 相互作用会减少肿瘤内的 T 细胞并加速肿瘤生长。因此，CD8 T 细胞上的 B7 配体可以在外周组织中顺式引发自主的 CD28 共刺激，这表明顺式信号转导是增强 T 细胞功能的一般机制。
