Caveolin-1 Triggers T-cell Activation via CD26 in Association with CARMA1

Abstract

CD26 is a widely distributed 110-kDa cell surface glycoprotein with an important role in T-cell costimulation. We demonstrated previously that CD26 binds to caveolin-1 in antigen-presenting cells, and following exogenous CD26 stimulation, Tollip and IRAK-1 disengage from caveolin-1 in antigen-presenting cells. IRAK-1 is then subsequently phosphorylated to up-regulate CD86 expression, resulting in subsequent T-cell proliferation. However, it is unclear whether caveolin-1 is a costimulatory ligand for CD26 in T-cells. Using soluble caveolin-1-Fc fusion protein, we now show that caveolin-1 is the costimulatory ligand for CD26, and that ligation of CD26 by caveolin-1 induces T-cell proliferation and NF-B activation in a T-cell receptor/ CD3-dependent manner. We also demonstrated that the cytoplasmic tail of CD26 interacts with CARMA1 in T-cells, resulting in signaling events that lead to NF-B activation. Ligation of CD26 by caveolin-1 recruits a complex consisting of CD26, CARMA1, Bcl10, and IB kinase to lipid rafts. Taken together, our findings provide novel insights into the regulation of T-cell costimulation via the CD26 molecule.

Hemagglutinating Virus of Japan Envelope Vectors as High-Performance Vehicles for Delivery of Small RNAs

“…Moreover, transfection of siRNAs into freshly isolated human T cells from healthy adult peripheral blood mononuclear cells demonstrated the role of CARD-containing MAGUK protein 1 on CD26-mediated T-cell co-stimulation. This study provided novel insights into the regulation of T-cell co-stimulation via CD26 [53].…”

CD26-Mediated Induction of EGR2 and IL-10 as Potential Regulatory Mechanism for CD26 Costimulatory Pathway

“…For T cell stimulation, anti-CD3 mAb (OKT3), anti-CD28 mAb (4B10), anti-CD26 mAb (1F7), and the fusion protein of the N-terminal domain of human caveolin-1 and human IgG1 Fc (Cav-Ig) developed in our laboratory were used (20). The following human-specific Abs were used for flow cytometry: FITC-labeled anti-LAG3 mAb (clone 17B4) and FITC-labeled mouse IgG1, k isotype control (clone MOPC-21) were purchased from Enzo Life Sciences (Farmingdale, NY).…”

“…siRNAs against EGR2 were purchased from Sigma-Aldrich, and negative control siRNA (oligonucleotide sequences are not disclosed) was purchased from Qiagen (Valencia, CA). Fifty picomoles siRNA duplexes were transfected into 5 3 10 5 purified CD4 + T cells by using HVJ-E vector (GenomONE-Si; Ishihara Sangyo Kaisha, Osaka, Japan) according to the manufacturer's instructions (19,20).…”

“…In addition to the ligand competition, the cytoplasmic domain of CTLA-4 associates with phosphatases SHP2 and PP2A to negatively regulate T cell activation, and it also inhibits the formation of lipid rafts (18). We have identified caveolin-1 on APCs as a functional ligand for CD26, and the ligation of CD26 with caveolin-1 recruits a complex consisting of CD26, CARMA1, Bcl10, MALT1, and IkB kinase to lipid rafts, leading to NF-kB activation (19,20). CD26 possesses DPPIV enzyme activity, able to cleave dipeptides from polypeptides with N-terminal penultimate proline or alanine.…”

Phenotyping of congenic dipeptidyl peptidase 4 (DP4) deficient Dark Agouti (DA) rats suggests involvement of DP4 in neuro-, endocrine, and immune functions

“…Besides differences in NK cell numbers and cytotoxicity, also a significantly diminished T-cell proliferative response was observed. In comparison to NK cells, a priori, it was more likely to find differences in this lymphocyte subpopulation, as T-cell functions might be affected at very different regulatory levels including, but not limited, to antigen presenting cell (APC)-T-cell interaction, T-cell co-stimulation, and memory function (41), tumor growth factor-b signaling (42,43), T-memory cell to regulatory T-cell (Treg) switch, or chemokine metabolisms (15,16). Here, we found in DP4 deficient animals a five-fold reduced proliferation rate upon stimulation with anti-ab-TCR ) rats was recorded over a period of 3 days.…”