UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

Characterization of CTLA4 Trafficking and Implications for Its Function

Khailaie, S; Rowshanravan, B; Robert, PA; Waters, E; Halliday, N; Herrera, JDB; Walker, LSK; ... Meyer-Hermann, M; + view all (2018) Characterization of CTLA4 Trafficking and Implications for Its Function. Biophysical Journal , 115 (7) pp. 1330-1343. 10.1016/j.bpj.2018.08.020. Green open access

[img]
Preview
Text
CTLA4_manuscript final.pdf - Accepted version

Download (1MB) | Preview

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.

Type: Article
Title: Characterization of CTLA4 Trafficking and Implications for Its Function
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.bpj.2018.08.020
Publisher version: http://doi.org/10.1016/j.bpj.2018.08.020
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inst for Liver and Digestive Hlth
URI: https://discovery.ucl.ac.uk/id/eprint/10060463
Downloads since deposit
27Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item