CTLA4 prohibits T cells from cross-dressing

Abstract

In this issue of JEM, Xiaozheng Xu et al. (2023. J. Exp. Med.https://doi.org/10.1084/jem.20221391) report that the inhibitory protein CTLA4 internalizes in cis the B7 stimulatory molecules previously "gnawed" by T cells from antigen-presenting cells (APCs) and in doing so prevents stimulatory T-T interactions.

Insights from Noémie Paillon and Claire Hivroz.

CTLA4-mediated cis-endocytosis of B7 ligands inhibits T–T stimulating interactions. Upper panel: CTLA4-negative T lymphocyte forming an immune synapse with an APC captures B7 and MHC-peptide (MHCp) molecules through CD28 (black bold arrow). This capture is stimulated by TCR triggering. The T cell is cross-dressed with B7 ligands and MHCp and can activate other T cells through T–T interactions. Lower panel: When the T lymphocyte expresses CTLA4, B7 ligands and MHCp are still captured by CD28 (black bold arrow) with a smaller contribution of CTLA4 to B7 capture (small black arrow). The B7 ligands are then cis-endocytosed by CTLA4 and degraded in lysosomal compartments. T–T interactions with these T cells presenting MHCp without CD28 ligands do not induce T cell stimulation. Figure created using Biorender.com.