title: Tumor necrosis factor-alpha induces coordinated changes in major histocompatibility class I presentation pathway, resulting in increased stability of class I complexes at the cell surface.
abstract: It is demonstrated that similar to interferon gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha) induces coordinated changes at different steps of the major histocompatibility complex (MHC) class I processing and presentation pathway in nonprofessional antigen-presenting cells (APCs). TNF-alpha up-regulates the expression of 3 catalytic immunoproteasome subunits--LMP2, LMP7, and MECL-1--the immunomodulatory proteasome activator PA28 alpha, the TAP1/TAP2 heterodimer, and the total pool of MHC class I heavy chain. It was also found that in TNF-alpha--treated cells, MHC class I molecules reconstitute more rapidly and have an increased average half-life at the cell surface. Biochemical changes induced by TNF-alpha in the MHC class I pathway were translated into increased sensitivity of TNF-alpha--treated targets to lysis by CD8(+) cytotoxic T cells, demonstrating improved presentation of at least certain endogenously processed MHC class I--restricted peptide epitopes. Significantly, it was demonstrated that the effects of TNF-alpha observed in this experimental system were not mediated through the induction of IFN-gamma. It appears to be likely that TNF-alpha--mediated effects on MHC class I processing and presentation do not involve any intermediate messengers. Collectively, these data demonstrate the existence of yet another biologic activity exerted by TNF-alpha, namely its capacity to act as a coordinated multi-step modulator of the MHC class I pathway of antigen processing and presentation. These results suggest that TNF-alpha may be useful when a concerted up-regulation of the MHC class I presentation machinery is required but cannot be achieved by IFN-gamma. (Blood. 2001;98:1108-1115)
authors.affiliation: Cancer Centrum Karolinska, Karolinska Institutet, Stockholm, Sweden.
authors.forename: K
authors.initials: K
authors.lastname: Hallermalm
authors.forename: K
authors.initials: K
authors.lastname: Seki
authors.forename: C
authors.initials: C
authors.lastname: Wei
authors.forename: C
authors.initials: C
authors.lastname: Castelli
authors.forename: L
authors.initials: L
authors.lastname: Rivoltini
authors.forename: R
authors.initials: R
authors.lastname: Kiessling
authors.forename: J
authors.initials: J
authors.lastname: Levitskaya
mesh_terms: D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters / Q000187:drug effects; D017951:Antigen Presentation / Q000187:drug effects*; D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000276:immunology; D000954:Antigens, Surface / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003546:Cysteine Endopeptidases / Q000187:drug effects; D004355:Drug Stability; D000939:Epitopes; D015395:Histocompatibility Antigens Class I / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D006801:Humans; D009097:Multienzyme Complexes; D010455:Peptides / Q000276:immunology; D046988:Proteasome Endopeptidase Complex; D011506:Proteins / Q000187:drug effects; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters; D000954:Antigens, Surface; D000939:Epitopes; D015395:Histocompatibility Antigens Class I; D009097:Multienzyme Complexes; D010455:Peptides; D011506:Proteins; C073119:TAP1 protein, human; D014409:Tumor Necrosis Factor-alpha; C071313:LMP-2 protein; C071692:TAP2 protein, human; D003546:Cysteine Endopeptidases; C077436:LMP7 protein; C098948:PSMB10 protein, human; D046988:Proteasome Endopeptidase Complex