Leukemia inhibitory factor inhibits plasmacytoid dendritic cell function and development

Renata Sesti-Costa, Luisa Cervantes-Barragan, Melissa K. Swiecki, José Luís Fachi, Marina Cella, Susan Gilfillan, Joao Santana Silva, Marco Colonna

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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-kB 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.

Original languageEnglish
Pages (from-to)2257-2268
Number of pages12
JournalJournal of Immunology
Volume204
Issue number8
DOIs
StatePublished - Apr 15 2020

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