Modulation of STAT1 protein levels: a mechanism shaping CD8 T-cell responses in vivo.
Type 1 interferons (IFNs) are induced in vivo, administered therapeutically, and potential targets for amelioration of autoimmune diseases. The cytokines mediate profound antiproliferative effects. Signal transducer and activator of transcription 1 (STAT1)-dependent signaling pathways are required for inhibition of proliferation, and viral infections can elicit high levels of type 1 IFNs as well as total STAT1 protein expression. Thus, a mechanism must be in place to help antigen-specific T cells overcome IFN-induced inhibition of proliferation. The studies reported here demonstrate that total CD8 T-cell proliferation in the presence of IFNs, ex vivo in response to cytokines and in vivo during viral infection, is inhibited through a STAT1-dependent mechanism. In contrast, major proportions of antigen-specific CD8, but not CD4, T cells are rendered less sensitive to this inhibition, express lower endogenous levels of total STAT1, and are selectively proliferating in the presence of type 1 IFN, at key times after viral challenge. Taken together, these novel results show that differential STAT1 expression is used by the immune system to modify cytokine-mediated effects on T-cell expansion and have implications for the consequences of therapeutic intervention in cytokine function.
Gil
M Pilar
MP
Department of Molecular Microbiology and Immunology, Brown University, Providence, RI 02912, USA.
Salomon
Rachelle
R
Louten
Jennifer
J
Biron
Christine A
CA
D000818:Animals; D000998:Antiviral Agents / Q000276:immunology / Q000494:pharmacology* / Q000627:therapeutic use; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects*; D007370:Interferon Type I / Q000276:immunology / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D014176:Protein Biosynthesis; D050794:STAT1 Transcription Factor / Q000096:biosynthesis* / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology; D014777:Virus Diseases / Q000188:drug therapy / Q000276:immunology
D000998:Antiviral Agents; D007370:Interferon Type I; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse