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TGF-? receptor maintains CD4 T helper cell identity during chronic viral infections.

ABSTRACT: Suppression of CD8 and CD4 T cells is a hallmark in chronic viral infections, including hepatitis C and HIV. While multiple pathways are known to inhibit CD8 T cells, the host molecules that restrict CD4 T cell responses are less understood. Here, we used inducible and CD4 T cell-specific deletion of the gene encoding the TGF-? receptor during chronic lymphocytic choriomeningitis virus infection in mice, and determined that TGF-? signaling restricted proliferation and terminal differentiation of antiviral CD4 T cells. TGF-? signaling also inhibited a cytotoxic program that includes granzymes and perforin expression at both early and late stages of infection in vivo and repressed the transcription factor eomesodermin. Overexpression of eomesodermin was sufficient to recapitulate in great part the phenotype of TGF-? receptor-deficient CD4 T cells, while SMAD4 was necessary for CD4 T cell accumulation and differentiation. TGF-? signaling also restricted accumulation and differentiation of CD4 T cells and reduced the expression of cytotoxic molecules in mice and humans infected with other persistent viruses. These data uncovered an eomesodermin-driven CD4 T cell program that is continuously suppressed by TGF-? signaling. During chronic viral infection, this program limits CD4 T cell responses while maintaining CD4 T helper cell identity.

SUBMITTER: Lewis GM

PROVIDER: S-EPMC5096797 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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TGF-β receptor maintains CD4 T helper cell identity during chronic viral infections.

Lewis Gavin M GM Wehrens Ellen J EJ Labarta-Bajo Lara L Streeck Hendrik H Zuniga Elina I EI

The Journal of clinical investigation 20160906 10

Suppression of CD8 and CD4 T cells is a hallmark in chronic viral infections, including hepatitis C and HIV. While multiple pathways are known to inhibit CD8 T cells, the host molecules that restrict CD4 T cell responses are less understood. Here, we used inducible and CD4 T cell-specific deletion of the gene encoding the TGF-β receptor during chronic lymphocytic choriomeningitis virus infection in mice, and determined that TGF-β signaling restricted proliferation and terminal differentiation of ...[more]

PMID: 27599295

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Project description:BackgroundshRNA lentiviral vectors are extensively used for gene knockdowns in mammalian cells, and non-target shRNAs typically are considered the proper experimental control for general changes caused by RNAi. However, the effects of non-target lentivirus controls on the modulation of cell signaling pathways remain largely unknown. In this study, we evaluated the effect of control lentiviral transduction on oxytocin receptor (OXTR) expression through the ERK/MAPK pathway in mouse and human skeletal muscle cells, on myogenic activity, and in vivo on mouse muscle regeneration. Furthermore, we mined published data for the influence of viral infections on OXTR levels in human populations and found that unrelated viral pathologies have a common consequence: diminished levels of OXTR.MethodsWe examined the change in OXTR mRNA expression upon transduction with control and Smad3-targeting viral vectors through real time RT-PCR and Western blotting, and confirmed with immunofluorescence. Changes in Smad3 and OXTR expression were examined both in vitro with mouse and human myoblasts and in vivo in mouse satellite cells. The general effects of viral infections on OXTR downregulation in humans were also examined by analyzing published Gene Expression Omnibus (GEO) datasets. The change in myoblast myogenic activity caused by the viral transduction (the percent of Pax7 + Ki67+ cells) was examined by immunofluorescence.ResultsResults shown in this work establish that lentiviral control vectors significantly downregulate OXTR expression at mRNA and protein levels and diminish key downstream effectors of OXTR, ERK signaling, reducing the myogenic proliferation of infected cells. This effect is evolutionarily conserved between mouse and human myogenic cells, and it manifests in satellite cells after control lentiviral transduction of mice in vivo. Furthermore, an examination of published datasets uncovered similar OXTR downregulation in humans that are afflicted with different viral infections. Additionally, cells transduced with Smad3-targeting shRNA downregulate OXTR even more than cells transduced with control viruses.ConclusionsOur work suggests that experimental cohorts transduced with control viruses may not behave the same as un-transduced cells and animals, specifically that control viral vectors significantly change the intensity of key cell-signaling pathways, such as OXTR/ERK. Our results further demonstrate that lentiviral transduction significantly decreases myogenic proliferation and suggest that viral infections in general may play a role in decreasing muscle health and regeneration, a decline in metabolic health, and a lower sense of well-being, as these rely on effective OXTR signaling. Additionally, our data suggest pathway crosstalk between TGF-β/pSmad3 and OXTR, implying that sustained attenuation of the TGF-β/pSmad3 pathway will reduce pro-regenerative OXTR/pERK signaling.

Dataset Information

TGF-? receptor maintains CD4 T helper cell identity during chronic viral infections.

Publications

TGF-β receptor maintains CD4 T helper cell identity during chronic viral infections.

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