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. 2004 Sep 28;101(39):14186-91.
doi: 10.1073/pnas.0405266101. Epub 2004 Sep 7.

VSports在线直播 - CD26 up-regulates expression of CD86 on antigen-presenting cells by means of caveolin-1

Kei Ohnuma  1 , Tadanori Yamochi, Masahiko Uchiyama, Kunika Nishibashi, Noritada Yoshikawa, Noriaki Shimizu, Satoshi Iwata, Hirotoshi Tanaka, Nam H Dang, Chikao Morimoto
Affiliations

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

Kei Ohnuma et al. Proc Natl Acad Sci U S A. .

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-kappaB, followed by up-regulation of CD86 VSports手机版. 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. .

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Figures

Fig. 1.
Fig. 1.
Purification and identification of CD26-binding proteins. (A) The indicated fractions were subjected to SDS/PAGE followed by silver staining. Proteins eluted from CD26-ADA Sepharose columns were identified by MS analysis, indicated on the right. (B) THP-1 cells cocultured with rsCD26 were immunoprecipitated (IP) with either anti-caveolin-1 (Left) or anti-CD26 Abs (Right). (C) The caveolin-1 SCD is necessary for binding to CD26. (D) Amino acids 201–211 and DPPIV of CD26 were required for binding of CD26 to caveolin-1.
Fig. 2.
Fig. 2.
CD26 on T cells interacts with caveolin-1 on monocytes. (A) rsCD26-TR was incubated with HEK293 cells transfected with GFP-fused wt caveolin-1. (Scale bar, 10 μm.) (B) Cav-TR was incubated with HEK293 cells transfected with GFP-fused wt CD26 (Scale bar, 10 μm.)
Fig. 3.
Fig. 3.
Caveolin-1 in monocytes was exposed to the cell surface after TT treatment and interacted with CD26 on activated T cells. To form cell–cell conjugation, activated T cells and TT-loaded monocytes were mixed and centrifuged. Conjugates were fixed without permeabilization and stained with anti-CD26 (FITC) and anti-cav-TR Abs. Three representative conjugates are shown (conj#1, conj#2, and conj#3). (Scale bars, 10 μm.)
Fig. 4.
Fig. 4.
CD26 induced phosphorylation of caveolin-1 in TT-loaded monocytes, followed by NF-κB activation. (A) Caveolin-1 on TT-loaded monocytes was bound to polystyrene latex beads coated with wt CD26 (Left) or deletion mutant CD26 lacking the CBD (del 201–211) (Right). (Scale bars, 10 μm.) (B) Caveolin-1 on TT-loaded monocytes was phosphorylated by stimulation with wt CD26-coated beads. (C) NF-κB level was increased in nuclear extracts from TT-loaded monocytes stimulated with CD26-coated beads. Data represent mean of OD at 655 nm ± SE from triplicate experiments. Asterisks show points of significant increase. STAT1, signal transducer and activator of transcription 1; PMA, phorbol 12-myristate 13-acetate. (D) After HEK293 cells were cotransfected with CD86-promoter luciferase constructs and wt caveolin-1-expressing vectors, wt rsCD26 or mutant rsCD26 del 201–211 was added to the culture media. Luciferase activity is shown as being relative to 1 μg of applied protein. Data represent mean ± SE from triplicate experiments. Asterisks indicate points of significant increase.
Fig. 5.
Fig. 5.
siRNA against caveolin-1 inhibited effect of CD26 on CD86 up-regulation in TT-loaded monocytes. (A) CD86 expression of caveolin-1 knock-down monocytes was not increased by CD26 stimulation. Data represent mean ± SE of five independent experiments. **, points of no significant change by sense siRNA. * and ***, points of significant increase. MFI, mean fluorescence intensity; SS1, sense 1; SS2, sense 2; mis, mismatched. (B) Purified monocytes were transfected with or without siRNA, followed by treatment with TT. After pulse with rsCD26, the preincubated monocytes were incubated with purified T cells from the same donor. Proliferation of T cells was monitored by measuring BrdUrd (BrdU) incorporation by ELISA. The degree of proliferation is indicated at OD450 with reference at OD690. The experiments represent mean values ± SE calculated from five independently performed experiments each from different donors. N.S., points of no significant change by mismatched siRNA. *, **, and ***, points of significant increase.
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