A CD26-controlled cell surface cascade for regulation of T cell motility and chemokine signals.
Chemokines are key regulators of cell trafficking, and dipeptidyl peptidase IV/CD26 (CD26) inactivates chemokines. Here we show that the CD26-processed chemokines SDF1alpha/CXCL12 and RANTES/CCL5, in contrast to a control chemokine not processed by CD26, are potent inducers of cell surface expression of thrombospondin-1 (TSP-1) in T lymphocytes through a CD26-controlled mechanism and that TSP-1 stimulates expression of lipoprotein receptor related protein/CD91. Accordingly, intact TSP-1 and a peptide mimetic of a sequence in TSP-1 were sufficient to stimulate CD91 expression. The chemokine-induced expression of TSP-1 and CD91 was mimicked by inhibitors of CD26 and CXCL12 and CCL5 as well as inhibitors of CD26 stimulated polarized cytoplasmic spreading and migration through TSP-1. Silencing of CD26 using small interfering RNA or Ab-induced modulation of CD26 also increased TSP-1 expression and enhanced cytoplasmic spreading and T cell migration markedly. These results indicate that CD26 is an endogenous inhibitor of T cell motility through inhibition of TSP-1 expression and that chemokines stimulate cell polarity and migration through abrogation of the CD26-dependent inhibition. This suggests that T cell motility is regulated by a cascade of interacting cell surface molecules.
Liu
Zhiwen
Z
Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institute at Karolinska University Hospital, Huddinge, Stockholm, Sweden.
Christensson
Marta
M
Forslöw
Anna
A
De Meester
Ingrid
I
Sundqvist
Karl-Gösta
KG
D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000378:metabolism; D054377:Chemokine CXCL12 / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism*; D002634:Chemotaxis, Leukocyte; D018819:Dipeptidyl Peptidase 4 / Q000502:physiology*; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000502:physiology; D019700:Thrombospondin 1 / Q000235:genetics*
C483024:CCL5 protein, human; D018946:Chemokine CCL5; D054377:Chemokine CXCL12; D018925:Chemokines; D008565:Membrane Proteins; D019700:Thrombospondin 1; D018819:Dipeptidyl Peptidase 4