STAT4 is required for the generation of Th1 and Th2, but not Th17 immune responses during monophosphoryl lipid A adjuvant activity

Oghumu, Steve; Natarajan, Gayathri; Kimble, Jennifer; Sperling, Rachel H.; Moretti, Ellen; Kaplan, Mark H.; Satoskar, Abhay R.

doi:10.1093/intimm/dxw038

Cited by 11 publications

(8 citation statements)

References 34 publications

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“…STAT4 signaling is induced by a number of cytokines including IL-12 and IL-2 [ 161 ] and is critical for IFNγ production during generation of Th1 responses [ 162 ]. STAT3 signaling is induced by a number of cytokines including IL-6 and OSM (and growth factors such as GM-CSF), with BCG vaccination recently shown to cause STAT3 phosphorylation in antigen presenting cells [ 163 ].…”

Section: Resultsmentioning

confidence: 99%

Injection site vaccinology of a recombinant vaccinia-based vector reveals diverse innate immune signatures

Hazlewood

Dumenil

et al. 2021

PLoS Pathog

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Poxvirus systems have been extensively used as vaccine vectors. Herein a RNA-Seq analysis of intramuscular injection sites provided detailed insights into host innate immune responses, as well as expression of vector and recombinant immunogen genes, after vaccination with a new multiplication defective, vaccinia-based vector, Sementis Copenhagen Vector. Chikungunya and Zika virus immunogen mRNA and protein expression was associated with necrosing skeletal muscle cells surrounded by mixed cellular infiltrates. The multiple adjuvant signatures at 12 hours post-vaccination were dominated by TLR3, 4 and 9, STING, MAVS, PKR and the inflammasome. Th1 cytokine signatures were dominated by IFNγ, TNF and IL1β, and chemokine signatures by CCL5 and CXCL12. Multiple signatures associated with dendritic cell stimulation were evident. By day seven, vaccine transcripts were absent, and cell death, neutrophil, macrophage and inflammation annotations had abated. No compelling arthritis signatures were identified. Such injection site vaccinology approaches should inform refinements in poxvirus-based vector design.

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Section: Resultsmentioning

confidence: 99%

Injection site vaccinology of a recombinant vaccinia-based vector reveals diverse innate immune signatures

Hazlewood

Dumenil

et al. 2021

PLoS Pathog

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“…STAT4 signaling is induced by a number of cytokines including IL-12 and IL-2 (Yang et al ., 2020) and is critical for IFNγ production during generation of Th1 responses (Varikuti et al ., 2016). STAT3 signaling is induced by a number of cytokines including IL-6 and OSM (and growth factors such as GM-CSF), with BCG vaccination recently shown to cause STAT3 phosphorylation in antigen presenting cells (Copland et al ., 2019).…”

Section: Resultsmentioning

confidence: 99%

Systems vaccinology analysis of a recombinant vaccinia-based vector reveals diverse innate immune signatures at the injection site

Hazlewood

Dumenil

et al. 2020

Preprint

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Poxvirus systems have been extensively used as vaccine vectors. Herein a systems vaccinology analysis of intramuscular injection sites provides detailed insights into host innate immune responses, as well as expression of vector and recombinant immunogen genes, after vaccination with a new multiplication defective, vaccinia-based vector, Sementis Copenhagen Vector. Chikungunya and Zika virus immunogen mRNA and protein expression was associated with necrosing skeletal muscle cells surrounded by mixed cellular infiltrates. Adjuvant signatures at 12 hours post-vaccination were dominated by TLR3, 4 and 9, STING, MAVS, PKR and the inflammasome. Th1 cytokine signatures were dominated by IFNγ, TNF and IL1β, and chemokine signatures by CCL5 and CXCL12. Multiple signatures associated with dendritic cell stimulation were evident. By day seven, vaccine transcripts were absent, and cell death, neutrophil, macrophage and inflammation annotations had abated. No compelling arthritis signatures were identified. Such innate systems vaccinology approaches should inform refinements in poxvirus-based vector design.

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“…Moreover, it was recently discovered that the silencing of STAT4 led to a reduction in the serum levels of IFN-γ and IL-2, with an elevation in the serum levels of IL-6 and IL-10 ( 43 ). IFN-γ production was lowered in STAT4 KO-derived splenocytes, but no significant differences in the levels of IL-12 and TNF-α were found when compared to those in WT mice ( 44 ). The effect of STAT4 reduction on VDR expression should be further elucidated in future studies.…”

Section: Discussionmentioning

confidence: 99%

‘Psoriasis�1’ reduces T‑lymphocyte‑mediated inflammation in patients with psoriasis by inhibiting vitamin�D receptor‑mediated STAT4 inactivation

et al. 2020

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Psoriasis is an immune-mediated dermatosis characterized by T-lymphocyte-mediated epidermal hyperplasia, for which there are currently no effective clinical treatments. 'Psoriasis 1' is a chinese herbal medicine formulation that has been recently used extensively in china for treating patients with psoriasis. However, the molecular mechanism of action of this potent formulation has not yet been fully elucidated. In the present study, the effects of 'Psoriasis 1' on T ymphocytes in patients with psoriasis were investigated and the underlying molecular mechanism was discussed. Blood samples were collected from 40 patients with psoriasis. ELISA was employed to assess the levels of tumour necrosis factor-α, interferon-γ, interleukin (IL)-2, IL-6, transforming growth factor-β, IL-4, IL-12, IL-23 and vitamin d (Vd). Western blot and quantitative PcR analyses were used to investigate the expression levels of Vd receptor (VdR) and signal transducer and activator of transcription (STAT)4 in T lymphocytes. 'Psoriasis 1' was observed to significantly increase CD4 + T cells. It also notably upregulated the mRNA and protein expression of VdR, and downregulated the mRNA and protein expression of STAT4. Moreover, the suppression of VdR was found to aggravate the inflammatory response, which was reversed by 'Psoriasis 1.' Thus, this formulation reportedly decreased the inflammation mediated by T lymphocytes in patients with psoriasis through inhibiting VdR-mediated STAT4 inactivation.

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STAT4 is required for the generation of Th1 and Th2, but not Th17 immune responses during monophosphoryl lipid A adjuvant activity

Cited by 11 publications

References 34 publications

Injection site vaccinology of a recombinant vaccinia-based vector reveals diverse innate immune signatures

Injection site vaccinology of a recombinant vaccinia-based vector reveals diverse innate immune signatures

Systems vaccinology analysis of a recombinant vaccinia-based vector reveals diverse innate immune signatures at the injection site

‘Psoriasis�1’ reduces T‑lymphocyte‑mediated inflammation in patients with psoriasis by inhibiting vitamin�D receptor‑mediated STAT4 inactivation

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