EFIS Lecture: Understanding the CTLA-4 checkpoint in the maintenance of immune homeostasis

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EFIS Lecture: Understanding the CTLA-4 checkpoint in the maintenance of immune homeostasis

Walker, LS; (2017) EFIS Lecture: Understanding the CTLA-4 checkpoint in the maintenance of immune homeostasis. Immunology Letters , 184 pp. 43-50. 10.1016/j.imlet.2017.02.007. Green open access

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Abstract

The past 20 years have heralded fascinating developments in the field of CTLA-4 biology. The CTLA-4 protein is a critical negative regulator of T cell immunity and its absence provokes severe lymphoproliferative disease. In a surprising twist, the generation of mixed bone marrow chimeric mice revealed that CTLA-4 predominantly functions in a cell-extrinsic manner, suggesting that CTLA-4 expressed on one cell can modify the behaviour of another cell. This was followed by the demonstration that CTLA-4 is highly expressed in regulatory T cells and can contribute to their suppressive activity. In line with a cell-extrinsic function, increasing evidence indicates that CTLA-4-positive cells can modify the phenotype of antigen presenting cells (APC), thereby regulating the priming of naive T cells. Notably, CTLA-4 is able to downregulate expression of costimulatory ligands on APC via a process of trans-endocytosis. The identification of patients with mutations in the ctla4 gene has provided an opportunity to study the contribution of CTLA-4 to Treg function and immune regulation in the human immune system. Finally, it has become apparent that CTLA-4 also plays a role in controlling humoral immunity, via the regulation of CD28-driven follicular helper T cell differentiation. At the recent German Society for Immunology congress, I discussed some of the contributions of my own lab to the unfolding of the CTLA-4 story, in the context of the work of others in the field. Despite the enormous clinical potential associated with modulation of the CTLA-4 pathway, including the use of soluble CTLA-4 molecules in autoimmune settings and blocking antibodies in cancer, it is clear there is still much to learn about this important pathway.

Type:	Article
Title:	EFIS Lecture: Understanding the CTLA-4 checkpoint in the maintenance of immune homeostasis
Location:	Netherlands
Open access status:	An open access version is available from UCL Discovery
DOI:	10.1016/j.imlet.2017.02.007
Publisher version:	http://doi.org/10.1016/j.imlet.2017.02.007
Language:	English
Additional information:	Copyright © 2017 Elsevier Ltd. All rights reserved. This is an Open Access article made available under a Creative Commons Attribution Non-commercial Non-derivative 4.0 International license (CC BY-NC-ND 4.0). This license allows you to share, copy, distribute and transmit the work for personal and non-commercial use providing author and publisher attribution is clearly stated. Further details about CC BY licenses are available at http://creativecommons.org/ licenses/by/4.0. Access may be initially restricted by the publisher.
Keywords:	CD28, CTLA-4, T-cells, autoimmunity, costimulation, tolerance
UCL classification:	UCL 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
URI:	https://discovery.ucl.ac.uk/id/eprint/1543056