Dipeptidyl peptidase IV (CD26) on T cells cleaves the CXC chemokine CXCL11 (I-TAC) and abolishes the stimulating but not the desensitizing potential of the chemokine.
Dipeptidyl peptidase IV (DPP IV/CD26) is a costimulatory molecule as well as a protease highly expressed on T cells. Purified DPP IV has been recognized to inactivate peptide hormones, neuropeptides, and some chemokines by cleavage behind a proline residue at the penultimate N-terminal amino acid position. Here, we identified another substrate for DPP IV among the chemokine family: the interferon-inducible T cell alpha chemoattractant (I-TAC/CXCL11). Using a specific DPP IV inhibitor, we demonstrate that DPP IV is responsible for the cleavage of the chemokine by PHA/IL-2-treated T cells. As PHA/IL-2-treated T cells also express the CXCL11 receptor (CXCR3), we investigated whether truncation of CXCL11 would modulate its biological activity for these cells. Truncated CXCL11 [CXCL11(3-73)] had an eightfold reduced potential to bind and to regulate CXCR3, but was completely inactive in calcium flux and chemotaxis assays. However, consistent with its reduced but still considerable ability to down-regulate CXCR3, truncated CXCL11 desensitized T cell chemotaxis in response to the intact chemokine. Hence, CXCL11-induced T cell recruitment may be regulated by DPP IV-mediated proteolytic inactivation of CXCL11 and furthermore by desensitization of T cells via the degradation product CXCL11(3-73).
Ludwig
Andreas
A
Department of Immunology and Cell Biology, Forschungszentrum Borstel, Parkallee 22, D-23845 Borstel, Germany.
Schiemann
Florian
F
Mentlein
Rolf
R
Lindner
Buko
B
Brandt
Ernst
E
D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D054371:Chemokine CXCL11; D019743:Chemokines, CXC / Q000378:metabolism* / Q000494:pharmacology; D002634:Chemotaxis, Leukocyte; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D004306:Dose-Response Relationship, Immunologic; D006801:Humans; D007700:Kinetics; D008213:Lymphocyte Activation; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000378:metabolism; D013601:T-Lymphocytes / Q000201:enzymology* / Q000276:immunology
C515202:CXCL11 protein, human; C515187:CXCR3 protein, human; D054371:Chemokine CXCL11; D019743:Chemokines, CXC; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; D018819:Dipeptidyl Peptidase 4; D002118:Calcium