title: Regulating type 1 IFN effects in CD8 T cells during viral infections: changing STAT4 and STAT1 expression for function.
abstract: Type 1 IFNs can conditionally activate all of the signal transducers and activators of transcription molecules (STATs), including STAT4. The best-characterized signaling pathways use STAT1, however, and type 1 IFN inhibition of cell proliferation is STAT1 dependent. We report that type 1 IFNs can basally stimulate STAT1- and STAT4-dependent effects in CD8 T cells, but that CD8 T cells responding to infections of mice with lymphocytic choriomenigitis virus have elevated STAT4 and lower STAT1 expression with significant consequences for modifying the effects of type 1 IFN exposure. The phenotype was associated with preferential type 1 IFN activation of STAT4 compared with STAT1. Stimulation through the TCR induced elevated STAT4 expression, and STAT4 was required for peak expansion of antigen-specific CD8 T cells, low STAT1 levels, and resistance to type 1 IFN-mediated inhibition of proliferation. Thus, a mechanism is discovered for regulating the consequences of type 1 IFN exposure in CD8 T cells, with STAT4 acting as a key molecule in driving optimal antigen-specific responses and overcoming STAT1-dependent inhibition of proliferation.
authors.affiliation: Department of Molecular Microbiology and Immunology, Brown University, Providence, RI 02903, USA.
authors.forename: M Pilar
authors.initials: MP
authors.lastname: Gil
authors.forename: Mickaël J Y
authors.initials: MJ
authors.lastname: Ploquin
authors.forename: Wendy T
authors.initials: WT
authors.lastname: Watford
authors.forename: Seung-Hwan
authors.initials: SH
authors.lastname: Lee
authors.forename: Kwangsin
authors.initials: K
authors.lastname: Kim
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Yuka
authors.initials: Y
authors.lastname: Kanno
authors.forename: John J
authors.initials: JJ
authors.lastname: O'Shea
authors.forename: Christine A
authors.initials: CA
authors.lastname: Biron
mesh_terms: D000818:Animals; D015153:Blotting, Western; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D005434:Flow Cytometry; D007370:Interferon Type I / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D060888:Real-Time Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000276:immunology* / Q000378:metabolism; D050797:STAT4 Transcription Factor / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D014777:Virus Diseases / Q000276:immunology* / Q000378:metabolism
chemical_list: D007370:Interferon Type I; D050794:STAT1 Transcription Factor; D050797:STAT4 Transcription Factor; C494080:Stat1 protein, mouse; C494091:Stat4 protein, mouse