Major histocompatibility complex class I restricted T-cell autoreactivity in human peripheral blood mononuclear cells.
During selection in the thymus or any subsequent response, T-cells recognize peptides bound to major histocompatibility complex (MHC) molecules. Peptides produced by lysosomes or by proteasome/immunoproteasome stimulate CD4+ or CD8+ T-cell, respectively. Inflammation alters components of both antigen-processing pathways resulting in the production of different peptides. The role of such changes in self/non-self discrimination was examined in autologous mixed peripheral blood mononuclear cell cultures. Stimulator cells were incubated in the presence or absence of INF-gamma, with or without lysosome inhibitors (ammonium chloride/chloroquine), cathepsin inhibitor (E-64), or proteasome/immunoproteasome inhibitor (epoxomicin). Responder cells were added and zeta-chain phosphorylated forms were used as read out. INF-gamma did not affect zeta-chain phosphorylated forms, which means that the expected INF-gamma induced alterations in antigen processing machinery do not influence self/non-self discrimination. Surprisingly, the completely phosphorylated 23-kDa zeta-chain was always present except in the case of epoxomicin, indicating the presence of MHC class I restricted autoreactive CD8+ T-cells but not of MHC class II restricted autoreactive CD4+ T-cells, possibly due to more efficient negative selection in the thymus of the latter. Autoimmunity is prevented due to absence of help by CD4+ T-cells. This conclusion was confirmed by the lack of differences in IL-2 levels in cell culture supernatants, as well as, by the absence of differences in cell proliferation under the various conditions described above.
Eleftheriadis
Theodoros
T
Research Laboratory, Theagenion Anticancer Hospital of Thessaloniki, Greece. elefthe@otenet.gr
Voyatzi
Soultana
S
Antoniadi
Georgia
G
Kartsios
Charalambos
C
Liakopoulos
Vassilios
V
Paraskevopoulos
Panagiotis
P
Galaktidou
Grammatiki
G
D015551:Autoimmunity / Q000276:immunology*; D049109:Cell Proliferation / Q000187:drug effects; D002469:Cell Separation; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D007376:Interleukin-2 / Q000378:metabolism; D008247:Lysosomes / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D061988:Proteasome Inhibitors; D013347:Subcellular Fractions; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*
D015395:Histocompatibility Antigens Class I; D007376:Interleukin-2; D061988:Proteasome Inhibitors; C071313:LMP-2 protein; D007371:Interferon-gamma; D003546:Cysteine Endopeptidases