ADAM17-dependent proteolysis of L-selectin promotes early clonal expansion of cytotoxic T cells

Mohammed, Rebar N., Wehenkel, Sophie C., Galkina, Elena V., Yates, Emma-Kate, Preece, Graham, Newman, Andrew, Watson, H. Angharad, Ohme, Julia, Bridgeman, John S., Durairaj, Ruban R. P., Moon, Owen R., Ladell, Kristin ORCID: https://orcid.org/0000-0002-9856-2938, Miners, Kelly L., Dolton, Garry, Troeberg, Linda, Kashiwagi, Masahide, Murphy, Gillian, Nagase, Hideaki, Price, David A. ORCID: https://orcid.org/0000-0001-9416-2737, Matthews, R. James, Knauper, Vera ORCID: https://orcid.org/0000-0002-3965-9924 and Ager, Ann ORCID: https://orcid.org/0000-0002-5763-8908 2019. ADAM17-dependent proteolysis of L-selectin promotes early clonal expansion of cytotoxic T cells. Scientific Reports 9 , 5487. 10.1038/s41598-019-41811-z

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Abstract

L-selectin on T-cells is best known as an adhesion molecule that supports recruitment of blood-borne naïve and central memory cells into lymph nodes. Proteolytic shedding of the ectodomain is thought to redirect activated T-cells from lymph nodes to sites of infection. However, we have shown that activated T-cells re-express L-selectin before lymph node egress and use L-selectin to locate to virus-infected tissues. Therefore, we considered other roles for L-selectin proteolysis during T cell activation. In this study, we used T cells expressing cleavable or non-cleavable L-selectin and determined the impact of L-selectin proteolysis on T cell activation in virus-infected mice. We confirm an essential and non-redundant role for ADAM17 in TCR-induced proteolysis of L-selectin in mouse and human T cells and show that L-selectin cleavage does not regulate T cell activation measured by CD69 or TCR internalisation. Following virus infection of mice, L-selectin proteolysis promoted early clonal expansion of cytotoxic T cells resulting in an 8-fold increase over T cells unable to cleave L-selectin. T cells unable to cleave L-selectin showed delayed proliferation in vitro which correlated with lower CD25 expression. Based on these results, we propose that ADAM17-dependent proteolysis of L-selectin should be considered a regulator of T-cell activation at sites of immune activity.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Dentistry Medicine
Additional Information:	This article is licensed under a Creative Commons Attribution 4.0 International License.
Publisher:	Nature Publishing Group
ISSN:	2045-2322
Funders:	Cancer Research UK
Date of First Compliant Deposit:	19 March 2019
Date of Acceptance:	12 March 2019
Last Modified:	22 Feb 2024 14:32
URI:	https://orca.cardiff.ac.uk/id/eprint/120885

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