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

• Published in: Scientific reports Vol. 9; no. 1; p. 5487
• Main Authors: 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, Kashiwagi, Masahide, Murphy, Gillian, Nagase, Hideaki, Price, David A., Matthews, R. James, Knäuper, Vera, Ager, Ann
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02.04.2019; Nature Publishing Group
• Subjects: 13; 13/106; 13/109; 13/31; 14; 14/34; 631/250/2152/1566/1618; 631/250/254; 64/60; ADAM17 Protein - genetics; ADAM17 Protein - metabolism; Animals; Antigens, CD - metabolism; Antigens, Differentiation, T-Lymphocyte - metabolism; CD25 antigen; CD69 antigen; Cell activation; Cell Movement; Cell proliferation; Cells, Cultured; Clone Cells - immunology; Cytotoxicity; Humanities and Social Sciences; Humans; Interleukin-2 Receptor alpha Subunit - metabolism; L-selectin; L-Selectin - genetics; L-Selectin - metabolism; Lectins, C-Type - metabolism; Lymph nodes; Lymphatic system; Lymphocyte Activation; Lymphocytes; Lymphocytes T; Memory cells; Mice; Mice, Inbred C57BL; multidisciplinary; Mutation; Proteolysis; Rodents; Science; Science (multidisciplinary); T cell receptors; T-Lymphocytes, Cytotoxic - immunology; Virus Diseases - immunology; Virus Diseases - metabolism
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-41811-z

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.