STAT3 Inhibits Autocrine IFN Signaling in Type I Conventional Dendritic Cells

Authors

Taylor T Chrisikos
Yifan Zhou
Laura M Kahn
Bhakti Patel
Nina L Denne
Athena Brooks
Li Shen
Jing Wang
Stephanie S Watowich

Publication Date

10-1-2022

Journal

Journal of Immunology

Abstract

Type I conventional dendritic cells (cDC1s) are an essential Ag-presenting population required for generating adaptive immunity against intracellular pathogens and tumors. While the transcriptional control of cDC1 development is well understood, the mechanisms by which extracellular stimuli regulate cDC1 function remain unclear. We previously demonstrated that the cytokine-responsive transcriptional regulator STAT3 inhibits polyinosinic:polycytidylic acid [poly(I:C)]-induced cDC1 maturation and cDC1-mediated antitumor immunity in murine breast cancer, indicating an intrinsic, suppressive role for STAT3 in cDC1s. To probe transcriptional mechanisms regulating cDC1 function, we generated novel RNA sequencing datasets representing poly(I:C)-, IL-10-, and STAT3-mediated gene expression responses in murine cDC1s. Bioinformatics analyses indicated that poly(I:C) stimulates multiple inflammatory pathways independent of STAT3, while IL-10-activated STAT3 uniquely inhibits the poly(I:C)-induced type I IFN (IFN-I) transcriptional response. We validated this mechanism using purified cDC1s deficient for STAT3 or IFN signaling. Our data reveal IL-10-activated STAT3 suppresses production of IFN-β and IFN-γ, accrual of tyrosine phosphorylated STAT1, and IFN-stimulated gene expression in cDC1s after poly(I:C) exposure. Moreover, we found that maturation of cDC1s in response to poly(I:C) is dependent on the IFN-I receptor, but not the type II IFN receptor, or IFN-λ. Taken together, we elucidate an essential role for STAT3 in restraining autocrine IFN-I signaling in cDC1s elicited by poly(I:C) stimulation, and we provide novel RNA sequencing datasets that will aid in further delineating inflammatory and anti-inflammatory mechanisms in cDC1s.

Keywords

Animals, Cytokines, Dendritic Cells, Interleukin-10, Mice, Poly I-C, STAT3 Transcription Factor, Tyrosine

DOI

10.4049/jimmunol.2101104

PMID

36038291

PMCID

PMC9529896

PubMedCentral® Posted Date

10-1-2023

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes