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

• Published in: Cellular and molecular life sciences : CMLS Vol. 77; no. 4; pp. 751 - 764
• Main Authors: Lettau, Marcus, Dietz, Michelle, Vollmers, Sarah, Armbrust, Fred, Peters, Christian, Dang, Thi Mai, Chitadze, Guranda, Kabelitz, Dieter, Janssen, Ottmar
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01-02-2020; Springer Nature B.V
• Subjects: Biochemistry; Biomarkers; Biomedical and Life Sciences; Biomedicine; Body fluids; Calcium; Calcium - metabolism; Calcium ions; Cell Biology; Cell Degranulation; Cell surface; Cells, Cultured; Chemokines; CXCL10 protein; Cytotoxicity; Deactivation; Degranulation; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Dipeptidyl Peptidase 4 - metabolism; Dipeptidyl-peptidase IV; Endopeptidases; Epithelial cells; Glucose; Glucose tolerance; Hormones; Humans; Immune system; Immunity; Immunological tolerance; Immunotherapy; Inactivation; Inhibitors; Life Sciences; Lymphocytes; Lymphocytes T; Neuropeptides; Organs; Original; Original Article; Peptidase; Perforin; Proteolysis; Secretory vesicles; Serine; Serine proteinase; Serum levels; T-Lymphocytes, Cytotoxic - physiology; Therapeutic applications; Toxicity; Tumors; Lymphocyte-mediated cytotoxicity; Dipeptidylpeptidase 4; NK cells; CD26; Secretory granules; T cells
• ISSN: 1420-682X; 1420-9071
• DOI: 10.1007/s00018-019-03207-0

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 Ca
2+
-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.