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

Sci Rep. 2019 Apr 2;9(1):5487. doi: 10.1038/s41598-019-41811-z.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM17 Protein / genetics
  • ADAM17 Protein / metabolism*
  • Animals
  • Antigens, CD / metabolism
  • Antigens, Differentiation, T-Lymphocyte / metabolism
  • Cell Movement
  • Cells, Cultured
  • Clone Cells / immunology*
  • Humans
  • Interleukin-2 Receptor alpha Subunit / metabolism
  • L-Selectin / genetics
  • L-Selectin / metabolism*
  • Lectins, C-Type / metabolism
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred C57BL
  • Mutation
  • Proteolysis
  • T-Lymphocytes, Cytotoxic / immunology*
  • Virus Diseases / immunology
  • Virus Diseases / metabolism*

Substances

  • Antigens, CD
  • Antigens, Differentiation, T-Lymphocyte
  • CD69 antigen
  • Interleukin-2 Receptor alpha Subunit
  • Lectins, C-Type
  • SELL protein, human
  • L-Selectin
  • ADAM17 Protein
  • ADAM17 protein, human
  • Adam17 protein, mouse