CTLA4 depletes T cell endogenous and trogocytosed B7 ligands via cis-endocytosis

J Exp Med. 2023 Jul 3;220(7):e20221391. doi: 10.1084/jem.20221391. Epub 2023 Apr 12.

Abstract

CD28 and CTLA4 are T cell coreceptors that competitively engage B7 ligands CD80 and CD86 to control adaptive immune responses. While the role of CTLA4 in restraining CD28 costimulatory signaling is well-established, the mechanism has remained unclear. Here, we report that human T cells acquire antigen-presenting-cell (APC)-derived B7 ligands and major histocompatibility complex (MHC) via trogocytosis through CD28:B7 binding. Acquired MHC and B7 enabled T cells to autostimulate, and this process was limited cell-intrinsically by CTLA4, which depletes B7 ligands trogocytosed or endogenously expressed by T cells through cis-endocytosis. Extending this model to the previously proposed extrinsic function of CTLA4 in human regulatory T cells (Treg), we show that blockade of either CD28 or CTLA4 attenuates Treg-mediated depletion of APC B7, indicating that trogocytosis and CTLA4-mediated cis-endocytosis work together to deplete B7 from APCs. Our study establishes CTLA4 as a cell-intrinsic molecular sink that limits B7 availability on the surface of T cells, with implications for CTLA4-targeted therapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abatacept / pharmacology
  • Antigens, CD / metabolism
  • Antigens, Differentiation
  • B7-1 Antigen / metabolism
  • B7-2 Antigen
  • CD28 Antigens* / metabolism
  • CTLA-4 Antigen / metabolism
  • Cell Adhesion Molecules
  • Humans
  • Immunoconjugates*
  • Ligands
  • Membrane Glycoproteins / metabolism

Substances

  • CTLA-4 Antigen
  • CD28 Antigens
  • Antigens, CD
  • Ligands
  • Antigens, Differentiation
  • Abatacept
  • B7-2 Antigen
  • Membrane Glycoproteins
  • Immunoconjugates
  • B7-1 Antigen
  • Cell Adhesion Molecules
  • CTLA4 protein, human