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, Miners, Kelly L, Dolton, Garry, Troeberg, Linda ORCID: https://orcid.org/0000-0003-0939-4651, Kashiwagi, Masahide, Murphy, Gillian, Nagase, Hideaki, Price, David A, Matthews, R James, Knäuper, Vera and Ager, Ann (2019) ADAM17-dependent proteolysis of L-selectin promotes early clonal expansion of cytotoxic T cells. Scientific Reports, 9. ISSN 2045-2322

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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
Faculty \ School:	Faculty of Medicine and Health Sciences > Norwich Medical School
UEA Research Groups:	Faculty of Medicine and Health Sciences > Research Groups > Musculoskeletal Medicine Faculty of Medicine and Health Sciences > Research Centres > Metabolic Health
Depositing User:	LivePure Connector
Date Deposited:	16 Apr 2019 12:30
Last Modified:	04 Mar 2024 17:47
URI:	https://ueaeprints.uea.ac.uk/id/eprint/70597
DOI:	10.1038/s41598-019-41811-z

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