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

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.

CTLA4 prohibits T cells from cross-dressing

“…Altogether, Xu et al (2023) reveal a new mechanism by which CTLA4-mediated cis-endocytosis depletes CD80/CD86 previously acquired in trans by CD28-mediated trogocytosis.…”

“…In their study, Xiaozheng Xu and co-workers addressed the questions of the precise role of CD28 and CTLA4 in T cell cross-dressing and of how CTLA4 regulates T–T communications ( Xu et al, 2023 ). They used CTLA4-expressing Jurkat leukemic T cells or human primary regulatory T cells (Tregs), which naturally express high amounts of CTLA4.…”

“…In contrast, once endocytosed, CTLA4 detaches from CD86 and recycles back to the cell surface to allow further trans-endocytosis ( Kennedy et al, 2022 ). Although Xu et al (2023) looked carefully at the presence of CD80 and CD86 in the endocytic compartments labeled by CTLA4, these compartments were not characterized in terms of intracellular identity. It would be interesting to study if the separate fates reported for the CTLA4-mediated CD80 and CD86 trans-endocytosis also happen for cis-endocytosis of CD80 and CD86.…”

“…Distinct from the trans-endocytosis model, the T cell-intrinsic model reported by Xu et al (2023) represents a new mechanism by which CTLA4 limits the amount and time that costimulatory molecules are displayed on the T cell surface. It probably mainly concerns Tregs cells that express high levels of CTLA4 but might also apply to effector T cells that express some CTLA4.…”

Monogenic forms of common variable immunodeficiency and implications on target therapeutic approaches

“…Cytotoxic T lymphocyte antigen 4 (CTLA-4) is a key T cell co-receptor which acts as a negative regulator in maintaining immune homeostasis by downregulating CD28:B7 ligands (CD80/CD86) interactions [ 31 ]. CTLA-4 plays its regulatory function both in a cell-extrinsic manner, where T-regulatory (T-reg) cells downregulate B7 by trans -endocytosis and degradation, and in a cell-intrinsic manner, by limiting B7 availability on the surface of T cells via cis -endocytosis [ 32 ▪ , 33 ]. CTLA-4 haploinsufficiency causes a severe CVID-like monogenic IEI with predominantly immune dysregulatory features characterized by progressive B cell exhaustion and hypogammaglobulinemia, multiorgan autoimmunity (immune cytopenia, enteropathy, endocrinopathies), and chronic lymphoproliferation with lymphocytic infiltrates in several organs (brain, gut, liver, and lung) [ 34 , 35 ].…”