cis-B7:CD28 interactions at invaginated synaptic membranes provide CD28 co-stimulation and promote CD8+ T cell function and anti-tumor immunity

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. [Display omitted] •T cell B7 molecules bind to CD28 in cis at concave membranes during CD28 endocytosis•cis-B7:CD28 interactions trigger CD28 signaling through PKCθ•CD28 cis-signaling is promoted by PI3K-SNX9-driven invagination of synaptic membranes•cis-B7:CD28 signaling enhances anti-tumor response of primed CD8+ T cells Classically, B7 ligands on antigen-presenting cells (APCs) activate the T cell co-stimulatory receptor, CD28. Zhao et al. reveal that B7 on T cells can activate CD28 in cis at endocytosis-associated membrane curvatures. This cis-signaling promotes anti-tumor T cell responses and explains how T cells sustain functionality in APC-sparse tissues.