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Review
. 2014 Oct;71(20):3873-83.
doi: 10.1007/s00018-014-1653-9. Epub 2014 May 31.

Interferon regulatory factor 3 in adaptive immune responses

Laure Ysebrant de Lendonck  1 , Valerie Martinet, Stanislas Goriely
Affiliations
Review

Interferon regulatory factor 3 in adaptive immune responses

Laure Ysebrant de Lendonck et al. Cell Mol Life Sci. 2014 Oct.

Abstract

Interferon regulatory factor (IRF) 3 plays a key role in innate responses against viruses. Indeed, activation of this transcription factor triggers the expression of type I interferons and downstream interferon-stimulated genes in infected cells. Recent evidences indicate that this pathway also modulates adaptive immune responses. This review focuses on the different mechanisms that are implicated in this process. We discuss the role of IRF3 within antigen-presenting cells and T lymphocytes in the polarization of the cellular immune response and its implication in the pathogenesis of immune disorders.

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Figures

Fig. 1
Fig. 1
Cytosolic recognition of nucleic acids leads to IRF3 activation. The presence of single/double-stranded RNA (ss/dsRNA) or double-stranded DNA (dsDNA) in the cytosol triggers TBK1 activation through specific cytosolic pattern-recognition systems involving IPS-1 or STING adaptor molecules, respectively. TBK1 induces the phosphorylation of IRF3 on specific serine residues, resulting in homo- (or hetero-) dimerization. Cytoplasmic dsDNA can be of microbial (intracellular bacteria or parasite, DNA virus such as HSV) or host (exogenous or endogenous DNA) origin. Several DNA sensors, such as IFI16, DDX41 or DAI have been reported. In addition, cytoplasmic DNA induces the production of cGAMP by the cyclase enzyme cGAS. cGAMP and the structurally related cyclic dinucleotides from intracellular bacteria directly activate the STING pathway. RNA will access the cytosol upon entry of RNA viruses in the cell or when genomic DNA from DNA viruses or intracellular bacteria is transcribed by an RNA polymerase such as RNA pol III. dsRNA is also a replication intermediate of both positive and negative RNA viruses. Cytoplasmic RNA is sensed by RLR helicases, such as RIG-I, MDA-5 or LGP2, that trigger IRF3 activation through the IPS-1 adaptor molecule (also known as MAVS). Several cofactors, such as β catenin, activated by LRRFIP1 upon recognition of cytoplasmic DNA or RNA, positively regulate IRF3 activity
Fig. 2
Fig. 2
TLR3 and TLR4 activation leads to IRF3 activation. Activation of TLR3 (by dsRNA) in the endosomal compartment leads to TBK1 activation in a TRIF-dependent fashion. Upon stimulation by LPS, TLR4 coupling to TRIF requires internalization of the receptor in the endosomal compartment in a CD14- and PI(3)K-dependent fashion
Fig. 3
Fig. 3
IRF3 contributes to the balance between IL-12 family members in antigen-presenting cells. IL-12 and IL-23 share a common chain (p40). IL-12 induces secretion of IFNγ by CD4 T (Th1), CD8 T and NK cells. IL-23 promotes IL-17 production by several T cell types including the Th17 subset. IL-27 shares homology with IL-12p70 and IL-23 and limits Th17 differentiation. Upon activation downstream of TLRs, IRF3 activates the transcription of IL-12p35 and IL-27p28 through direct recruitment to ISRE-binding sites within the promoter regions. IRF3 is also recruited to the IL-12/23p40 promoter and enhancer regions. For this gene, it leads to repression through competition with IRF5, a related transcription factor that is activated downstream of the MyD88-dependent pathway. Autocrine/paracrine IFNβ signaling further supports IL-12p35 and IL-27p28 gene expression through the upregulation of IRF1 (for both genes) and activation of ISGF3 (for IL-27p28 gene only)
Fig. 4
Fig. 4
IRF3 regulates the differentiation of CD8 T cells into IL-17-producing cells. Activation of CD8 T cells in the presence of IL-6 and TGFβ leads to upregulation of RORγt and differentiation into IL-17-producing cells (Tc17). IRF3 limits IL-17 production through direct interaction with RORγt in the cytoplasm. We suggest that IRF3 interferes with the shuttling of RORγt from the cytoplasm to the nucleus and hence its recruitment to DNA-binding sites. Classical IRF3 activation by poly(I:C) potentiates this repressive effect on RORγt, presumably through increased interaction in the nucleus
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