While B7 (CD80/CD86) on APCs is known to engage CD28 on T cells in head-to-head interactions in trans, Zhao et al. found that B7 on T cells similarly engaged CD28 in cis due to endocytosis-related proximity in the invaginating cell membrane. cis-B7:CD28 interactions released CD28 from membrane sequestration and activated CD28 signaling through PKCθ and PI3K binding. PI3K, which was not required for interactions in trans, recruited SNX9 and drove further CD28 endocytosis, thus promoting a positive feedback loop. cis-B7:CD28 signaling promoted cell-autonomous T cell survival, migration, and cytokine production, and contributed to T cell-mediated antitumor efficacy.
Contributed by Lauren Hitchings
ABSTRACT: 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 (PKC_) 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.
Author Info: (1) Department of Cell and Developmental Biology, School of Biological Sciences, University of California San Diego, La Jolla, CA 92093, USA. Electronic address: yuz798@ucsd.edu. (
Author Info: (1) Department of Cell and Developmental Biology, School of Biological Sciences, University of California San Diego, La Jolla, CA 92093, USA. Electronic address: yuz798@ucsd.edu. (2) Department of Pathology, University of California San Diego, La Jolla, CA 92093, USA. (3) Department of Cell and Developmental Biology, School of Biological Sciences, University of California San Diego, La Jolla, CA 92093, USA. (4) Department of Pathology, University of California San Diego, La Jolla, CA 92093, USA. (5) Department of Cell and Developmental Biology, School of Biological Sciences, University of California San Diego, La Jolla, CA 92093, USA. (6) Department of Cell and Developmental Biology, School of Biological Sciences, University of California San Diego, La Jolla, CA 92093, USA. (7) Department of Cell and Developmental Biology, School of Biological Sciences, University of California San Diego, La Jolla, CA 92093, USA. (8) Experimental Immunology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA. (9) Department of Pathology, University of California San Diego, La Jolla, CA 92093, USA. Electronic address: jbui@ucsd.edu. (10) Department of Cell and Developmental Biology, School of Biological Sciences, University of California San Diego, La Jolla, CA 92093, USA. Electronic address: enfuhui@ucsd.edu.
