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

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.

Citation

Rebar N Mohammed, Sophie C Wehenkel, Elena V Galkina, Emma-Kate Yates, Graham Preece, Andrew Newman, H Angharad Watson, Julia Ohme, John S Bridgeman, Ruban R P Durairaj, Owen R Moon, Kristin Ladell, Kelly L Miners, Garry Dolton, Linda Troeberg, Masahide Kashiwagi, Gillian Murphy, Hideaki Nagase, David A Price, R James Matthews, Vera Knäuper, Ann Ager. ADAM17-dependent proteolysis of L-selectin promotes early clonal expansion of cytotoxic T cells. Scientific reports. 2019 Apr 02;9(1):5487

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PMID: 30940840

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