Leukemia Inhibitory Factor Inhibits Plasmacytoid Dendritic Cell Function and Development [INNATE IMMUNITY AND INFLAMMATION]

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Abstract

Plasmacytoid dendritic cells (pDCs) produce abundant type I IFNs (IFN-I) in response to viral nucleic acids. Generation of pDCs from bone marrow dendritic cell (DC) progenitors and their maintenance is driven by the transcription factor E2-2 and inhibited by its repressor Id2. In this study, we find that mouse pDCs selectively express the receptor for LIF that signals through STAT3. Stimulation of pDCs with LIF inhibited IFN-I, TNF, and IL-6 responses to CpG and induced expression of the STAT3 targets SOCS3 and Bcl3, which inhibit IFN-I and NF-κB signaling. Moreover, although STAT3 has been also reported to induce E2-2, LIF paradoxically induced its repressor Id2. A late-stage bone marrow DC progenitor expressed low amounts of LIFR and developed into pDCs less efficiently after being exposed to LIF, consistent with the induction of Id2. Conversely, pDC development and serum IFN-I responses to lymphocytic choriomeningitis virus infection were augmented in newly generated mice lacking LIFR in either CD11c+ or hematopoietic cells. Thus, an LIF-driven STAT3 pathway induces SOCS3, Bcl3, and Id2, which render pDCs and late DC progenitors refractory to physiological stimuli controlling pDC functions and development. This pathway can be potentially exploited to prevent inappropriate secretion of IFN-I in autoimmune diseases or promote IFN-I secretion during viral infections.

Footnotes

  • This work was supported by Fundação de Amparo ao Estado de São Paulo Grants 2014/04044-5 and 2017/06577-9 (to R.S.-C. and J.L.F., respectively).

  • The microarray data presented in this article have been submitted to the National Center for Biotechnology Information Gene Expression Omnibus (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE138018) under accession number GSE138018.

  • The online version of this article contains supplemental material.

  • Abbreviations used in this article:

    BM
    bone marrow
    cDC
    conventional DC
    DC
    dendritic cell
    Dgkz
    diacylglycerol kinase ζ
    EuComm
    European Conditional Mouse Mutagenesis Consortium
    Flt3L
    Flt3 ligand
    Id2
    inhibitor of DNA binding 2
    Ier3
    immediate early response 3
    IFN-I
    type I IFN
    ImmGen
    Immunological Genome Project
    LCMV
    lymphocytic choriomeningitis virus
    MDP
    macrophage/DC precursor
    pDC
    plasmacytoid dendritic cell
    qRT-PCR
    quantitative RT-PCR
    Slpi
    secretory leukocyte peptidase inhibitor
    SOCS3
    suppressor of cytokine signaling 3.
  • Received May 28, 2019.
  • Accepted February 13, 2020.

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