Trans-endocytosis of CD80 and CD86: a molecular basis for the cell extrinsic function of CTLA-4

By O. Qureshi, Yong Zheng, Kyoko Nakamura, K. Attridge, Claire N. Manzotti, Emily M. Schmidt, Jennifer L Baker, L. Jeffery, S. Kaur, Zoe Briggs and 5 more. Science, 2011

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An inhibitory T cell receptor acts by stripping activating ligands off dendritic cells. Cytotoxic T lymphocyte antigen 4 (CTLA-4) is an essential negative regulator of T cell immune responses whose mechanism of action is the subject of debate. CTLA-4 shares two ligands (CD80 and CD86) with a stimulatory receptor, CD28. Here, we show that CTLA-4 can capture its ligands from opposing cells by a process of trans-endocytosis. After removal, these costimulatory ligands are degraded inside CTLA-4–expressing cells, resulting in impaired costimulation via CD28. Acquisition of CD86 from antigen-presenting cells is stimulated by T cell receptor engagement and observed in vitro and in vivo. These data reveal a mechanism of immune regulation in which CTLA-4 acts as an effector molecule to inhibit CD28 costimulation by the cell-extrinsic depletion of ligands, accounting for many of the known features of the CD28–CTLA-4 system.

Subfields: Immunology

View Paper: https://www.semanticscholar.org/paper/f9e2866b5b376c4e12bc92181936f3364606f0b8

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In Immunology

Citations in the corpus

CD28 costimulation: from mechanism to therapy (2016, background): “CTLA4 contributes to Treg cell function by decreasing CD80 and CD86 expression on dendritic cells (Qureshi et al., 2011; Wing et al., 2008).”
Regulatory T Cells and Human Disease. (2020, background): “TregCTLA4 not only competes withCD28 forCD80/CD86 binding but also appears to depleteCD80/CD86 molecules from the cell surface of APCs by transendocytosis (73).”
Anti-CTLA-4 Antibodies of IgG2a Isotype Enhance Antitumor Activity through Reduction of Intratumoral Regulatory T Cells (2013, background): “trol of T-cell function by Tregs and Teffs occurs through the ability of CTLA-4–positive cells to remove B7 ligands on antigen-presenting cells, thereby limiting their costimulatory potential (12, 13).”
Immune Checkpoint Inhibitors in Cancer Therapy (2022, background): “Treg cells produce CTLA-4 constitutively because it is a target gene of the forkhead transcription factor FOXP3 [78], whose expression determines the Treg cell lineage [79].”
Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022, background): “Additionally, CTLA-4 could capture, remove, and degrade its ligands CD80/CD86 from nearby APCs by trans-endocytosis, further hampering the co-stimulatory signal [125].”
Regulatory T Cells: Mechanisms of Differentiation and Function (2012, background): “It was suggested that in BALB/c mice, known for their susceptibility to various immune-mediated disorders, the reduced suppression capacity of CTLA-4deficient Treg cells is due to their inability to downregulate CD80 and CD86 via transendocytosis (203, 205).”