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 antige...

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Bibliographic Details
Published in:Cellular Immunology 2006-03, Vol.240 (1), p.62-67
Main Authors: Eleftheriadis, Theodoros, Voyatzi, Soultana, Antoniadi, Georgia, Kartsios, Charalambos, Liakopoulos, Vassilios, Paraskevopoulos, Panagiotis, Galaktidou, Grammatiki
Format: Article
Language:English
Subjects:
Antigen processing
Autoimmunity - immunology
Cell Proliferation - drug effects
Cell Separation
Cells, Cultured
Cysteine Endopeptidases - metabolism
Histocompatibility Antigens Class I - immunology
Humans
Interferon-gamma - pharmacology
Interferon-γ
Interleukin-2 - secretion
Lysosomes - drug effects
Phosphorylation - drug effects
Proteasome
Proteasome Inhibitors
Self-tolerance
Subcellular Fractions
T-Lymphocytes - cytology
T-Lymphocytes - immunology
ζ-chain
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Summary: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-γ, with or without lysosome inhibitors (ammonium chloride/chloroquine), cathepsin inhibitor (E-64), or proteasome/immunoproteasome inhibitor (epoxomicin). Responder cells were added and ζ-chain phosphorylated forms were used as read out. INF-γ did not affect ζ-chain phosphorylated forms, which means that the expected INF-γ induced alterations in antigen processing machinery do not influence self/non-self discrimination. Surprisingly, the completely phosphorylated 23-kDa ζ-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.
ISSN:0008-8749
1090-2163
1365-2567
DOI:10.1016/j.cellimm.2006.06.006