title: 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-kappaB. Binding of CD26 to caveolin-1 therefore regulates signaling pathways in antigen-presenting cells to induce antigen-specific T-cell proliferation.
authors.affiliation: Department of Clinical Immunology, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Minato-ku, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Ohnuma
authors.forename: Tadanori
authors.initials: T
authors.lastname: Yamochi
authors.forename: Masahiko
authors.initials: M
authors.lastname: Uchiyama
authors.forename: Kunika
authors.initials: K
authors.lastname: Nishibashi
authors.forename: Satoshi
authors.initials: S
authors.lastname: Iwata
authors.forename: Osamu
authors.initials: O
authors.lastname: Hosono
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawasaki
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Tanaka
authors.forename: Nam H
authors.initials: NH
authors.lastname: Dang
authors.forename: Chikao
authors.initials: C
authors.lastname: Morimoto
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000378:metabolism*; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D051940:B7-2 Antigen; D051242:Caveolin 1; D022461:Caveolins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002522:Chlorocebus aethiops; D018819:Dipeptidyl Peptidase 4 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D009000:Monocytes / Q000378:metabolism; D019000:Phosphotyrosine / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D011494:Protein Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D013745:Tetanus Toxoid / Q000276:immunology / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D015703:Antigens, CD; D051940:B7-2 Antigen; C495540:CAV1 protein, human; C497964:CD86 protein, human; D051242:Caveolin 1; D022461:Caveolins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D034741:RNA, Small Interfering; C410602:TOLLIP protein, human; D013745:Tetanus Toxoid; D019000:Phosphotyrosine; D011494:Protein Kinases; D053592:Interleukin-1 Receptor-Associated Kinases; D018819:Dipeptidyl Peptidase 4