title: Proteasome inhibition suppresses essential immune functions of human CD4+ T cells.
abstract: The proteasome constitutes the central proteolytic component of the highly conserved ubiquitin-proteasome system, which is required for the maintenance and regulation of basic cellular processes, including differentiation, proliferation, cell cycling, gene transcription and apoptosis. Here we show that inhibition of proteasomal proteolytic activity by the proteasome inhibitors bortezomib and lactacystin suppresses essential immune functions of human CD4(+) T cells activated by allogeneic dendritic cells (DCs). In activated CD4(+) T cells, proteasome inhibition induces apoptosis accompanied by rapid accumulation and stabilization of the tumour suppressor protein p53. Activated CD4(+) T cells surviving proteasome inhibition undergo inhibition of proliferation by induction of G(1) phase cell-cycle arrest. Induction of G(1) arrest is accompanied by the accumulation of cyclin-dependent kinase inhibitors p21(WAF1/CIP1) and p27(KIP1) and the disappearance of cyclin A, cyclin D2 and proliferating cell nuclear antigen, proteins known to regulate G(1) to S phase cell-cycle transitions. Expression of the activation-associated cell surface receptors CD25, CD28, CD120b and CD134 as well as production of interferon-gamma (IFN-gamma), tumour necrosis factor-alpha (TNF-alpha), interleukin-4 (IL-4) and IL-5 is suppressed in response to proteasome inhibition in CD4(+) T cells activated by DCs. Expression of CD25, IFN-gamma, TNF-alpha, IL-4 and IL-5 is known to be mediated by the transcriptional activity of nuclear factor of activated T cells (NFAT), and we show here that proteasome inhibition suppresses activation and nuclear translocation of NFATc2 in activated CD4(+) T cells. Thus, the proteasome is required for essential immune functions of activated CD4(+) T cells and can be defined as a molecular target for the suppression of deregulated and unwanted T-cell-mediated immune responses.
authors.affiliation: Department of Transplantation Immunology, Institute of Immunology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Berges
authors.forename: Heinrich
authors.initials: H
authors.lastname: Haberstock
authors.forename: Dominik
authors.initials: D
authors.lastname: Fuchs
authors.forename: Marion
authors.initials: M
authors.lastname: Miltz
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Sadeghi
authors.forename: Gerhard
authors.initials: G
authors.lastname: Opelz
authors.forename: Volker
authors.initials: V
authors.lastname: Daniel
authors.forename: Cord
authors.initials: C
authors.lastname: Naujokat
mesh_terms: D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D015703:Antigens, CD / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D004306:Dose-Response Relationship, Immunologic; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D050778:NFATC Transcription Factors / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000276:immunology; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000494:pharmacology; D014178:Translocation, Genetic / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D001897:Boronic Acids; D018797:Cell Cycle Proteins; D016207:Cytokines; D007166:Immunosuppressive Agents; D050778:NFATC Transcription Factors; C494006:NFATC2 protein, human; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011719:Pyrazines; D016159:Tumor Suppressor Protein p53; C067713:lactacystin; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex; D000111:Acetylcysteine