CD26 up-regulates expression of CD86 on antigen-presenting cells by means of caveolin-1

Abstract

CD26 is a T cell costimulatory molecule with dipeptidyl peptidase IV activity in its extracellular region. We previously reported that recombinant soluble CD26 enhanced T cell proliferation induced by the recall antigen tetanus toxoid (TT). However, the mechanism involved in this enhancement is not yet elucidated. We now demonstrate that CD26 binds Caveolin-1 on antigen-presenting cells, and that residues 201-211 of CD26 along with the serine catalytic site at residue 630 contribute to binding to caveolin-1 scaffolding domain. In addition, after CD26 -caveolin-1 interaction on TT-loaded monocytes, caveolin-1 is phosphorylated, which links to activate NF-B, followed by up-regulation of CD86. Finally, reduced caveolin-1 expression on monocytes inhibits CD26-mediated CD86 up-regulation and abrogates CD26 effect on TT-induced T cell proliferation. Taken together, these results strongly suggest that CD26 -caveolin-1 interaction plays a role in the up-regulation of CD86 on TT-loaded monocytes and subsequent engagement with CD28 on T cells, leading to antigen-specific T cell activation. C D26 is a widely distributed, 110-kDa cell-surface glycoprotein with known dipeptidyl peptidase IV (DPPIV) (EC 3.4.14.5) activity in its extracellular domain (1, 2), capable of cleaving amino-terminal dipeptides with either L-proline or L-alanine at the penultimate position. The CD4 ϩ CD26 high T cells respond maximally to recall antigens, such as tetanus toxoid (TT) (3). Crosslinking of CD26 and CD3 with solid-phase immobilized mAbs induces T cell costimulation and IL-2 production by either human CD4 ϩ T cells or CD26 Jurkat transfectants (4, 5, 6). Importantly, DPPIV enzyme activity is required for CD26-mediated T cell costimulation (7). More recently, we have shown that internalization of CD26 after crosslinking is mediated in part by the mannose-6-phosphate͞ insulin-like growth factor II receptor (M6P͞IGF-IIR), and that CD26-M6P͞IGFIIR interaction plays a role in CD26-induced T cell costimulation (8).Caveolin-1 was first identified as a major tyrosine phosphorylated protein in v-Src-transformed chicken embryo fibroblasts (9). Multiple lines of evidence suggest that caveolin-1 acts as a scaffolding protein capable of directly interacting with and modulating the activity of caveolin-bound signaling molecules. In support of this hypothesis, caveolin-1 binding can functionally modulate the activity of G protein-coupled proteins, membrane proteins, nonreceptor tyrosine and serine͞threonine kinases, protein kinase C isoforms, epidermal growth factor receptor, and endothelial nitric oxide synthetase (10, 11). In immune cells, caveolin-1 on monocytes͞ macrophages regulates metabolism of scavenged lipids (12). However, it is unknown whether caveolin-1 also plays a role in signal transduction in antigen-presenting cells (APC).Maximal T cell activation requires both an antigen-specific stimulus provided by an MHC peptide complex and a costimulatory signal (13). Engagement of CD28 on T cell surface by B7-1 (CD80) or B7-2 (CD86) expressed on AP...

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

“…Moreover, we showed that residues 201-211 of CD26 along with the serine catalytic site at residue 630, which constitute a pocket structure of CD26/DP-PIV, contribute to binding to caveolin-1 scaffolding domain (14). More recently, we demonstrated that caveolin-1 binds to Tollip (Toll-interacting protein) and IRAK-1 (interleukin-1 receptor associated serine/threonine kinase 1) in the membrane of tetanus toxoid-loaded monocytes, and following exogenous CD26 stimulation, Tollip and IRAK-1 disengage from caveolin-1, with IRAK-1 being subsequently phosphorylated to up-regulate CD86 expression (15).…”

“…In our previous study (14), we identified caveolin-1 in antigen-presenting cells (APC) as a binding protein for CD26, and we demonstrated that CD26 on activated memory T-cells directly faces caveolin-1 on tetanus toxoid-loaded monocytes in the contact area, which was revealed as the immunological synapse for T-cell-APC interaction. Moreover, we showed that residues 201-211 of CD26 along with the serine catalytic site at residue 630, which constitute a pocket structure of CD26/DP-PIV, contribute to binding to caveolin-1 scaffolding domain (14).…”

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

“…Caveolin-1 is a ubiquitously expressed ligand of CD26 in many cell types such as epithelial cells, endothelial cells, fibroblasts, macrophages, and neutrophils. We have previously shown that caveolin-1 was detected on the cell surface of monocytes 12-24 h after Ag uptake, and that CD26 and caveolin-1 colocalized at the T cell/ monocyte contact site (19). Moreover, caveolin-1 expression is regulated by NF-kB, and stimulation with LPS or TNF-a increases the expression of caveolin-1 mRNA and protein (54), suggesting that expression of caveolin-1 may be increased on cells accumulated at sites of inflammation, leading to the transduction of intensive CD26-mediated signaling in CD26 + T cells.…”

“…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.…”