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

Mohammed, Rebar N, Wehenkel, Sophie C, Galkina, E, Yates, E, Preece, G, Newman, Andrew, Watson, Angharad, Ohme, Julia, Bridgeman, John S, Durairaj, Ruban, Moon, Owen, Ladell, Kristin, Miners, Kelly, Dolton, Garry, Troeberg, L, Kashiwagi, M, Murphy, G, Nagase, H, Price, David A, Matthews, R James, Knauper, V and Ager, Ann 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
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: 05 Aug 2019 13:42
URI: http://orca-mwe.cf.ac.uk/id/eprint/120885

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