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Differential ligand binding/trafficking for distinct CTLA-4 fates: is it an expandable mechanism?

Cellular & Molecular Immunology volume 20, pages 1–2 (2023)Cite this article

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Autoimmunity and cancer progression occur as immune cells lose their ability to distinguish healthy self-cells or control the outgrowth of malignant cells. Immune dysfunction results from limited antigen recognition, immune suppression, or functional remodeling of immune cells [2]. The inflammatory properties of autoimmune diseases are similar to those of early-stage cancer but different from those of advanced cancer. Therefore, the incidence of various cancers is elevated in patients with preexisting autoimmune diseases [3].

T-cell–mediated immunity can be regulated by the CD28–CTLA-4 system, which comprises a network of positive and negative costimulatory signals, the integration of which modulates T-cell responses such as activation, proliferation, and cytotoxicity [4]. CTLA-4 mediates the inhibition of T-cell responses by competing with the costimulatory receptor CD28 for CD80 and CD86, depleting the ligands from the surfaces of cells such as APCs and dendritic cells (DCs) through TE, and delivering inhibitory signals via its intracellular tail [4]. Although the roles of CD80 and CD86 are considered redundant, Kennedy et al. revealed a substantial difference in the fate of CTLA-4. CTLA-4 binds strongly to dimeric CD80 independent of intracellular pH, whereas it binds weakly to monomeric CD86 in a pH-sensitive manner. This results in differential subcellular trafficking either to late endosomes/lysosomes (degradative fate) or to the plasma membrane (recycling fate). Recycled CTLA-4 captures and removes additional CD86 on APCs to establish immune tolerance.

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  1. These authors contributed equally: Ji Eon Kim, Eunmi Kim.

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  1. Department of Pharmacy, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea

    Ji Eon Kim, Eunmi Kim & Jung Weon Lee

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  1. Ji Eon Kim
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Correspondence to Jung Weon Lee.

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Kim, J.E., Kim, E. & Lee, J.W. Differential ligand binding/trafficking for distinct CTLA-4 fates: is it an expandable mechanism?. Cell Mol Immunol 20, 1–2 (2023). https://doi.org/10.1038/s41423-022-00945-3

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