Plasmin and regulators of plasmin activity control the migratory capacity and adhesion of human T cells and dendritic cells by regulating cleavage of the chemokine CCL21.
The homeostatic chemokine CCL21 has a pivotal role in lymphocyte homing and compartment localisation within the lymph node, and also affects adhesion between immune cells. The effects of CCL21 are modulated by its mode of presentation, with different cellular responses seen for surface-bound and soluble forms. Here we show that plasmin cleaves surface-bound CCL21 to release the C-terminal peptide responsible for CCL21 binding to glycosaminoglycans on the extracellular matrix and cell surfaces, thereby generating the soluble form. Loss of this anchoring peptide enabled the chemotactic activity of CCL21 and reduced cell tethering. Tissue plasminogen activator did not cleave CCL21 directly but enhanced CCL21 processing through generation of plasmin from plasminogen. The tissue plasminogen activator inhibitor neuroserpin prevented processing of CCL21 and blocked the effects of soluble CCL21 on cell migration. Similarly, the plasmin-specific inhibitor α2-antiplasmin inhibited CCL21-mediated migration of human T cells and dendritic cells and tethering of T cells to APCs. We conclude that the plasmin system proteins plasmin, tissue plasminogen activator and neuroserpin regulate CCL21 function in the immune system by controlling the balance of matrix- and cell-bound CCL21.
School of Biological Sciences, University of Auckland, Auckland, New Zealand.|Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand.
Natalie
0000-0002-5480-1714
N
Lorenz
School of Biological Sciences, University of Auckland, Auckland, New Zealand.|Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand.
Evert Jan
EJ
Loef
School of Biological Sciences, University of Auckland, Auckland, New Zealand.|Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand.
Inken D
ID
Kelch
School of Biological Sciences, University of Auckland, Auckland, New Zealand.|Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand.
Daniel J
DJ
Verdon
School of Biological Sciences, University of Auckland, Auckland, New Zealand.
Moyra M
MM
Black
School of Biological Sciences, University of Auckland, Auckland, New Zealand.|Auckland Science Analytical Services, University of Auckland, Auckland, New Zealand.
Martin J
MJ
Middleditch
School of Biological Sciences, University of Auckland, Auckland, New Zealand.|Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand.
David R
DR
Greenwood
Centre for Brain Research, Rangahau Roro, Aotearoa, New Zealand.|School of Medical Sciences, University of Auckland, Auckland, New Zealand.
E Scott
ES
Graham
School of Biological Sciences, University of Auckland, Auckland, New Zealand.|Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand.
Anna Es
AE
Brooks
School of Biological Sciences, University of Auckland, Auckland, New Zealand.|Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand.
P Rod
PR
Dunbar
School of Biological Sciences, University of Auckland, Auckland, New Zealand.|Centre for Brain Research, Rangahau Roro, Aotearoa, New Zealand.|Brain Research New Zealand, Rangahau Roro, Aotearoa, New Zealand.
Nigel P
NP
Birch
D000595:Amino Acid Sequence; D002448:Cell Adhesion / Q000187:drug effects; D002450:Cell Communication / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects*; D054421:Chemokine CCL21 / Q000737:chemistry / Q000378:metabolism*; D003713:Dendritic Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D009479:Neuropeptides / Q000494:pharmacology; D010958:Plasminogen / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D011994:Recombinant Proteins / Q000378:metabolism; D015843:Serpins / Q000494:pharmacology; D013601:T-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D010959:Tissue Plasminogen Activator / Q000494:pharmacology; D000979:alpha-2-Antiplasmin / Q000494:pharmacology; D000097522:Neuroserpin
D054421:Chemokine CCL21; D009479:Neuropeptides; D010958:Plasminogen; D011994:Recombinant Proteins; D015843:Serpins; D010959:Tissue Plasminogen Activator; D000979:alpha-2-Antiplasmin; D000097522:Neuroserpin; C515478:CCL21 protein, human