Masahiko Uchiyama

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

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-κB 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-κB activation. Ligation of CD26 by caveolin-1 recruits a complex consisting of CD26, CARMA1, Bcl10, and IκB kinase to lipid rafts. Taken together, our findings provide novel insights into the regulation of T-cell costimulation via the CD26 molecule.

CD26 Mediates Dissociation of Tollip and IRAK-1 from Caveolin-1 and Induces Upregulation of CD86 on Antigen-Presenting Cells

ABSTRACT CD26 is a T-cell costimulatory molecule with dipeptidyl peptidase IV enzyme activity in its extracellular region. We have previously reported that the addition of recombinant soluble CD26 resulted in enhanced proliferation of human T lymphocytes induced by the recall antigen tetanus toxoid (TT) via upregulation of CD86 on monocytes and that caveolin-1 was a binding protein of CD26, and the CD26-caveolin-1 interaction resulted in caveolin-1 phosphorylation (p-cav-1) as well as TT-mediated T-cell proliferation. However, the mechanism involved in this immune enhancement has not yet been elucidated. In the present work, we perform experiments to identify the molecular mechanisms by which p-cav-1 leads directly to the upregulation of CD86. Through proteomic analysis, we identify Tollip (Toll-interacting protein) and IRAK-1 (interleukin-1 receptor-associated serine/threonine kinase 1) as caveolin-1-interacting proteins in monocytes. We also demonstrate that following stimulation by exogenous CD26, Tollip and IRAK-1 dissociate from caveolin-1, and IRAK-1 is then phosphorylated in the cytosol, leading to the upregulation of CD86 via activation of NF-κB. Binding of CD26 to caveolin-1 therefore regulates signaling pathways in antigen-presenting cells to induce antigen-specific T-cell proliferation.

SS-A/Ro52, an Autoantigen Involved in CD28-Mediated IL-2 Production

An autoantibody against SS-A/Ro52 (Ro52) is most frequently found in the sera of patients with Sjögren’s syndrome, systemic lupus erythematosus, and congenital heart block from anti-Ro52 Ab-positive mother. However, the physiological function of the autoantigen SS-A/Ro52 has not yet been elucidated. In this study, we describe the role of Ro52 protein in T cell activation. Overexpression of SS-A/Ro52 in Jurkat T cell resulted in enhanced IL-2 production following CD28 stimulation. Furthermore, transfection of anti-Ro52-specific small RNA duplexes partially blocked the expression of native and overexpressed Ro52 in Jurkat T cell, resulting in decreased IL-2 production via CD28 pathway in these cells. Finally, intracellular localization of Ro52 dramatically changed following CD28 stimulation. Our data reveal a novel function of Ro52 in CD28-mediated pathway, which eventually contributes to cytokine production and expression of the T cell biological programs.

T-cell activation via CD26 and caveolin-1 in rheumatoid synovium

CD26 is a T-cell costimulatory molecule with dipeptidyl peptidase IV (DPPIV) activity in its extracellular region. We previously reported that recombinant soluble CD26 enhances peripheral blood T-cell proliferation induced by the recall antigen tetanus toxoid (TT). Recently, we demonstrated that CD26 binds caveolin-1 on antigen-presenting cell (APC), and that residues 201–211 of CD26 along with the serine catalytic site at residue 630, which constitute a pocket structure of CD26/DPPIV, contribute to binding to caveolin-1 scaffolding domain. In addition, following CD26–caveolin-1 interaction on TT-loaded monocytes, caveolin-1 is phosphorylated, with linkage to NF-κB activation, followed by upregulation of CD86. Finally, reduced caveolin-1 expression on APC inhibits CD26-mediated CD86 upregulation and abrogates CD26 effect on TT-induced T-cell proliferation, and immunohistochemical studies revealed an infiltration of CD26+ T cells in the sublining region of rheumatoid synovium and high expression of caveolin-1 in the increased vasculature and synoviocytes of the rheumatoid synovium. Taken together, these results strongly suggest that CD26–cavolin-1 interaction plays a role in the upregulation of CD86 on TT-loaded APC and subsequent engagement with CD28 on T cells, leading to antigen-specific T-cell activation such as the T-cell-mediated antigen-specific response in rheumatoid arthritis.

Stereoselective synthesis of optically active perhydrofuro[2,3-b]furan derivatives

(1R,5S)-2,8-Dioxabicyclo[3.3.0]octan-3-one and its derivatives, important subunits in various biologically active natural products, have been synthesized based on a new approach using the asymmetric oxyselenenylation of 2,3-dihydrofuran as the key step.

G1/S cell cycle arrest provoked in human T cells by antibody to CD26.

CD26 is T cell costimulatory molecule with dipeptidyl peptidase IV (DPPIV) enzyme activity located in its extracellular region. The expression of CD26 is enhanced after activation of T cells, while it is preferentially expressed on a subset of CD4+ memory T cells in the resting state. In this paper, we demonstrate that binding of the soluble anti‐CD26 monoclonal antibody (mAb) 1F7 inhibits human T‐cell growth and proliferation in both CD26‐transfected Jurkat T‐cell lines and human T‐cell clones by inducing G1/S arrest, which is associated with enhancement of p21Cip1 expression. This effect depends on the DPPIV enzyme activity of the CD26 molecule. Moreover, we show that expression of p21Cip1 after treatment with the anti‐CD26 mAb 1F7 appears to be induced through activation of extracellular signal‐regulated kinase (ERK) pathway. These data thus suggest that anti‐CD26 treatment may have potential use in the clinical setting involving activated T cell dysregulation, including autoimmune disorders and graft‐vs.‐host disease.

A simple enantioselective synthesis of (R)- and (S)-1,7-dioxaspiro[5.5]undecane via intramolecular asymmetric oxyselenenylation: a new route to optically active spiroketals

Abstract Both enantiomers of 1,7-dioxaspiro[5.5]undecane, the major pheromone components of the olive fruit fly ( Bactrocea oleae ), have been synthesized by using a new method based on the intramolecular asymmetric oxyselenenylation of 4-(3,4-dihydro-2 H -pyran-6-yl)butan-1-ol.

Asymmetric methoxyselenenylation of alkyl vinyl ethers: a new route to chiral acetals

Abstract The asymmetric methoxyselenenylation of alkyl vinyl ethers afforded the corresponding chiral acetals with moderate to good diastereoselectivity. This reaction and subsequent deselenenylation provided a new method of preparing enantiomerically enriched acetals in which the acetal carbon was the only stereogenic center.

Blockade of CD26-mediated T cell costimulation with soluble caveolin-1-Ig fusion protein induces anergy in CD4+T cells.

CD26 binds to caveolin-1 in antigen-presenting cells (APC), and that ligation of CD26 by caveolin-1 induces T cell proliferation in a TCR/CD3-dependent manner. We report herein the effects of CD26-caveolin-1 costimulatory blockade by fusion protein caveolin-1-Ig (Cav-Ig). Soluble Cav-Ig inhibits T cell proliferation and cytokine production in response to recall antigen, or allogeneic APC. Our data hence suggest that blocking of CD26-associated signaling by soluble Cav-Ig may be an effective approach as immunosuppressive therapy.

Stereoselective total syntheses of (±)-arthrinone and related natural compounds

The first total syntheses of (±)-arthrinone, (±)-1-dehydroxyarthrinone, and (±)-3a,9a-deoxy-3a-hydroxy-1-dehydroxyarthrinone, antifungal metabolites from the coprophilous fungus Cercophora sordarioides, were accomplished in a stereoselective manner. The ring systems of these metabolites, which were rare among natural products, were efficiently and diastereoselectively assembled using the [2,3]Wittig rearrangement and Diels–Alder reaction as the key steps.