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Degranulation of human cytotoxic lymphocytes is a major source of proteolytically active soluble CD26/DPP4

  • Marcus LettauEmail author
  • Michelle Dietz
  • Sarah Vollmers
  • Fred Armbrust
  • Christian Peters
  • Thi Mai Dang
  • Guranda Chitadze
  • Dieter Kabelitz
  • Ottmar Janssen
Original Article

Abstract

Dipeptidyl peptidase 4 (DPP4, CD26) is a serine protease detected on several immune cells and on epithelial cells of various organs. Besides the membrane-bound enzyme, a catalytically active soluble form (sCD26/DPP4) is detected in several body fluids. Both variants cleave off dipeptides from the N-termini of various chemokines, neuropeptides, and hormones. CD26/DPP4 plays a fundamental role in the regulation of blood glucose levels by inactivating insulinotropic incretins and CD26/DPP4 inhibitors are thus routinely used in diabetes mellitus type 2 therapy to improve glucose tolerance. Such inhibitors might also prevent the CD26/DPP4-mediated inactivation of the T-cell chemoattractant CXCL10 released by certain tumors and thus improve anti-tumor immunity and immunotherapy. Despite its implication in the regulation of many (patho-)physiological processes and its consideration as a biomarker and therapeutic target, the cellular source of sCD26/DPP4 remains highly debated and mechanisms of its release are so far unknown. In line with recent reports that activated T lymphocytes could be a major source of sCD26/DPP4, we now demonstrate that CD26/DPP4 is stored in secretory granules of several major human cytotoxic lymphocyte populations and co-localizes with effector proteins such as granzymes, perforin, and granulysin. Upon stimulation, vesicular CD26/DPP4 is rapidly translocated to the cell surface in a Ca2+-dependent manner. Importantly, activation-induced degranulation leads to a massive release of proteolytically active sCD26/DPP4. Since activated effector lymphocytes serve as a major source of sCD26/DPP4, these results might explain the observed disease-associated alterations of sCD26/DPP4 serum levels and also indicate a so far unknown role of CD26/DPP4 in lymphocyte-mediated cytotoxicity.

Keywords

CD26 Dipeptidylpeptidase 4 Secretory granules T cells NK cells Lymphocyte-mediated cytotoxicity 

Notes

Acknowledgements

This work was supported by the Deutsche Forschungsgemeinschaft [DFG, Grant Numbers JA 610 7/1 (to OJ) and Ka 502/19-1 (to DK)]; the Medical Faculty of the University of Kiel; and the Cluster of Excellence Exc 306 ‘Inflammation-at-Interfaces’ Cluster Lab VII. We thank Ina Martens for expert technical assistance. This work forms part of the master theses of FA and SV and the MD theses of MD and TMD.

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

Supplementary material

18_2019_3207_MOESM1_ESM.pdf (184 kb)
Supplementary material 1 (PDF 184 kb)
18_2019_3207_MOESM2_ESM.pdf (284 kb)
Supplementary material 2 (PDF 283 kb)

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Authors and Affiliations

  1. 1.Institute of ImmunologyChristian-Albrechts University Kiel and University Hospital Schleswig-HolsteinKielGermany
  2. 2.Medical Department II, Unit for Hematological DiagnosticsUniversity Hospital Schleswig-HolsteinKielGermany

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