A CD26-Controlled Cell Surface Cascade for Regulation of T Cell Motility and Chemokine Signals

Abstract

Chemokines are key regulators of cell trafficking, and dipeptidyl peptidase IV/CD26 (CD26) inactivates chemokines. Here we show that the CD26-processed chemokines SDF1α/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.

Human MAIT cells are xenobiotic-resistant, tissue-targeted, CD161hi IL-17–secreting T cells

“…MAIT cells expressed very high level of CD26, a dipeptidase able to process several chemokine and peptidic mediators. [21][22][23][24] Like most memory CD8 T cells, MAIT cells expressed heterogeneous levels of NKp80, high levels of NKG2D, and 2 SLAM family members, CD150 and CD244, although they do not depend on these pathways for their development contrary to NKT cells. 3,25 The pattern of chemokine receptor expression was, however, very specific, as MAIT cells exhibited high levels of CCR6 and CXCR6, heterogeneous levels of CXCR4, and intermediate expression of CCR9.…”

The dietary flavonoid apigenin enhances the activities of the anti-metastatic protein CD26 on human colon carcinoma cells

“…The intrinsic enzyme activity of CD26, dipeptidyl peptidase IV (DPPIV), allows the cleavage of a number of chemokines and other peptides involved in cell regulation, of which the major substrates are CXCL12 (stromalderived factor-1, SDF-1), glucagon-like-peptides and RANTES (CCL5) [18][19][20]. This creates a key regulatory node for processes involved in immune disorders, diabetes, HIV and cancer [17,[21][22][23].…”

Dipeptidyl Peptidase IV in Inflammatory Bowel Diseases (DPP IV/CD26)

“…Pripisivala joj se jedinstvena uloga u metabolizmu polipeptida s visokim sadržajem prolina. Brojnim daljnjim istraživanjima utvrđena je njezina važna uloga i u imunosnom odgovoru organizma (65). Nakon dobivenih saznanja o biološkim učincima važnih bioaktivnih molekula, supstrata DPP IV/CD26 te mogućnosti njihove aktivacije odnosno inaktivacije, što dovodi do modulacije neuroimunobiokemijskog odgovora organizma, istraživanja vezana uz ovu molekulu eksponencijalno su rasla (66).…”

“…Molekula DPP IV/CD26 prva je membranski vezana peptidaza za koju je utvrđena uloga u procesu prijenosa signala u stanicu. Kako ovaj transmembranski glikoprotein sadržava kratku citoplazmatsku domenu, iako bez uobičajenih signalnih motiva (65,77), vjeruje se da su upravo taj kratki transmembranski dio i unutarstanični dio uključeni u kaskadne reakcije prijenosa signala u stanicu. Različite grupe istraživača opisale su uključenost DPP IV/CD26 u regulaciju diferencijacije i rasta limfocita T, kao i njihove aktivacije (82,101,102).…”