Modulation of the expression of the IFN-gamma receptor beta-chain controls responsiveness to IFN-gamma in human peripheral blood T cells.
IFN-gamma has potent antiproliferative and apoptotic effects in T cells that are important in determining T cell development and polarized differentiation. Therefore, any event that enables T cells to become less responsive to IFN- gamma may potentially alter immune responsiveness to Ag. In this work, we show that human peripheral blood T cells that are stimulated through the TCR and expanded with IL-2 are unresponsive to IFN-gamma, as determined by a lack of activation of jak kinases and the transcription factor, STAT1(alpha), a signal transducer and activator of transcription. This nonresponsiveness occurs because of a lack of expression of the beta- chain (accessory factor) of the IFN-gamma receptor, while at the same time maintaining IFN-gamma receptor alpha-chain expression. Expression of the beta-chain can be restored by secondary TCR ligation or PMA treatment. T cell blasts treated with PMA are now responsive to IFN-gamma. When freshly isolated, highly enriched (>98%) T cells are examined for IFN-gamma responsiveness; these cells can respond to IFN-gamma and express beta-chain. Therefore, as T cells progress from primary TCR activation through IL-2-dependent proliferation, followed by secondary TCR stimulation, their responsiveness to IFN-gamma varies, and this may affect their ability to participate in an ongoing immune response.
Sakatsume
M
M
Food and Drug Administration, Center for Biologics Research and Evaluation, Division of Cytokine Biology, Bethesda, MD 20892, USA.
Finbloom
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D015703:Antigens, CD / Q000737:chemistry / Q000187:drug effects / Q000235:genetics*; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D002455:Cell Division / Q000187:drug effects; D017931:DNA Primers / Q000235:genetics; D015870:Gene Expression; D006801:Humans; D066298:In Vitro Techniques; D050832:Interferon-Stimulated Gene Factor 3; D007371:Interferon-gamma / Q000494:pharmacology*; D008969:Molecular Sequence Data; D011487:Protein Conformation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017471:Receptors, Interferon / Q000737:chemistry / Q000187:drug effects / Q000235:genetics*; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism; D000096743:Interferon gamma Receptor
D015703:Antigens, CD; D017931:DNA Primers; D050832:Interferon-Stimulated Gene Factor 3; D007371:Interferon-gamma; D012333:RNA, Messenger; D017471:Receptors, Interferon; D013755:Tetradecanoylphorbol Acetate; D014157:Transcription Factors; D000096743:Interferon gamma Receptor; C079868:gamma interferon activation factor