Characterization of CTLA4 Trafficking and Implications for Its Function

Abstract

CTLA4 is an essential negative regulator of T-cell immune responses and a key checkpoint regulating autoimmunity and antitumor responses. Genetic mutations resulting in quantitative defects in the CTLA4 pathway are also associated with the development of immune dysregulation syndromes in humans. It has been proposed that CTLA4 functions to remove its ligands CD80 and CD86 from opposing cells by a process known as transendocytosis. A quantitative characterization of CTLA4 synthesis, endocytosis, degradation, and recycling and how these affect its function is currently lacking. In a combined in vitro and in silico study, we developed a mathematical model and identified these trafficking parameters. Our model predicts optimal ligand removal in an intermediate affinity range. The intracellular CTLA4 pool as well as fast internalization, recovery of free CTLA4 from internalized complexes, and recycling is critical for sustained functionality. CD80-CTLA4 interactions are predicted to dominate over CD86-CTLA4. Implications of these findings in the context of control of antigen-presenting cells by regulatory T cells and of pathologic genetic deficiencies are discussed. The presented mathematical model can be reused in the community beyond these questions to better understand other trafficking receptors and study the impact of CTLA4 targeting drugs.

Transcriptomic Study of Porcine Small Intestine Epithelial Cells Reveals Important Genes and Pathways Associated With Susceptibility to Escherichia coli F4ac Diarrhea

“…Moreover, the expression of CTLA4 was up-regulated in the comparison of non-adhesive (non-infected) and adhesive (infected) small intestine epithelial cells, which is in consistent with many previous studies in humans and animals (Walker and Sansom, 2015;Khailaie et al, 2018;Xiang et al, 2018). The involvement of CTLA4 ( Supplementary Table S13) in cell adhesion and T cell receptor signaling pathway might also play positive role in immune related-response (Manley, 2013).…”

CTLA-4–mediated transendocytosis of costimulatory molecules primarily targets migratory dendritic cells

“…Notably, multiscale spatiotemporal modelling of T cell-APC interactions suggests that simple ligand competition by CTLA-4 is not sufficient to interrupt CD28 engagement, with TE being required to effectively eliminate the costimulatory signal (21). Additional mathematical modelling indicates that ligands need to be of optimal affinity to maximise TE, and that the process is a quantitative one, dictated by expression levels of ligands and receptors (22, 23). Tregs from humans with heterozygous CTLA-4 deficiency show a quantitative defect in TE and suppressive function (5), while in model systems where APCs have been subjected to TE, ligand loss is proportional to the number of CTLA-4-expressing cells and the amount of remaining ligand directly correlates with the number of T cells that can be induced to proliferate (23).…”

An Integrative Network Modeling Approach to T CD4 Cell Activation

“…Stimulation of the TCR and CD28 in the context of the continuous contact of CD28 with co-stimulatory molecules (CD80/86) leads to the expression of CTLA-4 dimers (CTLA-4dim), which in turn displaces CD28 from the CD80/86 ligands and imparts inhibitory signals over multiple steps in the activation cascade (Vandenborre et al, 1999;Khailaie et al, 2018). CTLA-4 dimers have greater affinity for CD80/86 than CD28 and thus overwhelms the co-stimulatory signal.…”