Commensal Bacteria Calibrate the Activation Threshold of Innate Antiviral Immunity

Abt, Michael C.; Osborne, Lisa C.; Monticelli, Laurel A.; Doering, Travis A.; Alenghat, Theresa; Sonnenberg, Gregory F.; Paley, Michael; Antenus, Marcelo; Williams, Katie; Erikson, Jan; Wherry, E. John; Artis, David

doi:10.1016/j.immuni.2012.04.011

Cited by 857 publications

(983 citation statements)

References 64 publications

Supporting

Mentioning

897

Contrasting

Unclassified

Order By: Relevance

“…This observation is similar to what has been reported in a viral infection model, in which gut bacteria induced APC "poising" [91]. In agreement, germ-free or antibiotic-treated mice, which completely lack or have a compromised commensal microbiota, showed defective innate immunity during viral infection [92,93]. Furthermore, in the tumor context, germ-free mice and antibiotic-treated mice were resistant to anti-CTLA-4 therapy [94].…”

Section: Functional Interaction With the Commensal Microbiotasupporting

confidence: 86%

Innate immune signaling and regulation in cancer immunotherapy

et al. 2016

View full text Add to dashboard Cite

A pre-existing T cell-inflamed tumor microenvironment has prognostic utility and also can be predictive for response to contemporary cancer immunotherapies. The generation of a spontaneous T cell response against tumor-associated antigens depends on innate immune activation, which drives type I interferon (IFN) production. Recent work has revealed a major role for the STING pathway of cytosolic DNA sensing in this process. This cascade of events contributes to the activation of Batf3-lineage dendritic cells (DCs), which appear to be central to anti-tumor immunity. Non-T cell-inflamed tumors lack chemokines for Batf3 DC recruitment, have few Batf3 DCs, and lack a type I IFN gene signature, suggesting that failed innate immune activation may be the ultimate cause for lack of spontaneous T cell activation and accumulation. With this information in hand, new strategies for triggering innate immune activation and Batf3 DC recruitment are being developed, including novel STING agonists for de novo immune priming. Ultimately, the successful development of effective innate immune activators should expand the fraction of patients that can respond to immunotherapies, such as with checkpoint blockade antibodies.

show abstract

Section: Functional Interaction With the Commensal Microbiotasupporting

confidence: 86%

Innate immune signaling and regulation in cancer immunotherapy

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Of note, another important source of tonic type I IFN production can origin via PRR-dependent mechanisms in myeloid cells of the gut. In this regard, it has been shown that commensal microbiota provide an important source of PRR ligands under steady state that are important to facilitate antiviral immunity [32][33][34]. While we can exclude this route of paracrine priming in our in vitro assays, this mode of action might be of relevance for optimal pDC responses in vivo.…”

Section: Discussionmentioning

confidence: 95%

Self‐priming determines high type I IFN production by plasmacytoid dendritic cells

et al. 2014

View full text Add to dashboard Cite

Plasmacytoid dendritic cells (pDCs) are responsible for the robust and immediate production of type I IFNs during viral infection. pDCs employ TLR7 and TLR9 to detect RNA and CpG motifs present in microbial genomes. CpG-A was the first synthetic stimulus available that induced large amounts of IFN-α (type I IFN) in pDCs. CpG-B, however, only weakly activates pDCs to produce IFN-α. Here, we demonstrate that differences in the kinetics of TLR9 activation in human pDCs are essential for the understanding of the functional difference between CpG-A and CpG-B. While CpG-B quickly induces IFN-α production in pDCs, CpG-A stimulation results in delayed yet maximal IFN-α induction. Constitutive production of low levels of type I IFN in pDCs, acting in a paracrine and autocrine fashion, turned out to be the key mechanism responsible for this phenomenon. At high cell density, pDC-derived, constitutive type I IFN production primes pDCs for maximal TLR responsiveness. This accounts for the high activity of higher structured TLR agonists that trigger type I IFN production in a delayed fashion. Altogether, these data demonstrate that high type I IFN production by pDCs cannot be simply ascribed to cell-autonomous mechanisms, yet critically depends on the local immune context. Keywords:CpG-A r CpG-B r pDC r TLR9 r Type I IFN Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionThe recognition of invading pathogens and the initiation of an appropriate immune response are key functions of the innate immune system. TLRs are a family of PRRs that sense conserved microbial signatures, also known as PAMPs [1,2]. Among these, TLR9 detects unmethylated CpG-motifs, which are present in viral Correspondence: Prof. Veit Hornung e-mail: veit.hornung@uni-bonn.de and bacterial DNA, whereas TLR7 senses uridine-rich RNA. To prevent recognition of endogenous nucleic acids, both TLR7 and TLR9 are confined to endosomal compartments that are usually devoid of nucleic acids. While both TLR7 and TLR9 are broadly expressed in innate immune cells of the murine system, both TLR7 and TLR9 show a far more restricted expression pattern within the human system, with TLR9 expression restricted to B cells and pDCs. * These authors equally contributed to this work.C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 808Sarah Kim et al. Eur. J. Immunol. 2014. 44: 807-818 TLR9 traffics from the endoplasmic reticulum through the Golgi apparatus to acidic endosomal compartments, where it is proteolytically cleaved to achieve its signaling-competent state. Following ligand engagement, TLR9 initiates a signaling cascade, which is dependent on MyD88. In pDCs, MyD88 triggers a signaling complex consisting of IRAK1/4, TRAF3, and IKKα that leads to phosphorylation and nuclear translocation of interferon regulatory factor 7 (IRF7) and transcription of type I IFN genes. At the same time, TLR9 engagement activates NF-κB and subsequent proinflammatory gene expression [3]. For TLR9, di...

show abstract

“…Autoclaved drinking water was supplemented with ampicillin (0.5 mg/mL), gentamicin (0.5 mg/mL), metronidazole (0.5 mg/mL), neomycin (0.5 mg/mL), and vancomycin (0.25 mg/mL) 7 d before Treg ablation and/or C. albicans inoculation and continued for the duration of the experiment as described (27). Recombinant C. albicans expressing I-A b :2W1S 52-68 peptide or the parental strain (SC5314) (31) were grown in yeast extract peptone dextrose plus acetate (YPAD) media, washed and resuspended in saline, and inoculated by oral gavage (2 × 10 6 cfu in 20 μL).…”

Section: Methodsmentioning

confidence: 99%

Commensal microbes drive intestinal inflammation by IL-17–producing CD4 ⁺ T cells through ICOSL and OX40L costimulation in the absence of B7-1 and B7-2

Luo¹,

Jiang²,

Chaturvedi³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The costimulatory B7-1 (CD80)/B7-2 (CD86) molecules, along with T-cell receptor stimulation, together facilitate T-cell activation. This explains why in vivo B7 costimulation neutralization efficiently silences a variety of human autoimmune disorders. Paradoxically, however, B7 blockade also potently moderates accumulation of immune-suppressive regulatory T cells (Tregs) essential for protection against multiorgan systemic autoimmunity. Here we show that B7 deprivation in mice overrides the necessity for Tregs in averting systemic autoimmunity and inflammation in extraintestinal tissues, whereas peripherally induced Tregs retained in the absence of B7 selectively mitigate intestinal inflammation caused by Th17 effector CD4 + T cells. The need for additional immune suppression in the intestine reflects commensal microbe-driven T-cell activation through the accessory costimulation molecules ICOSL and OX40L. Eradication of commensal enteric bacteria mitigates intestinal inflammation and IL-17 production triggered by Treg depletion in B7-deficient mice, whereas re-establishing intestinal colonization with Candida albicans primes expansion of Th17 cells with commensal specificity. Thus, neutralizing B7 costimulation uncovers an essential role for Tregs in selectively averting intestinal inflammation by Th17 CD4 + T cells with commensal microbe specificity.

show abstract

Commensal Bacteria Calibrate the Activation Threshold of Innate Antiviral Immunity

Cited by 857 publications

References 64 publications

Innate immune signaling and regulation in cancer immunotherapy

Innate immune signaling and regulation in cancer immunotherapy

Self‐priming determines high type I IFN production by plasmacytoid dendritic cells

Commensal microbes drive intestinal inflammation by IL-17–producing CD4 ⁺ T cells through ICOSL and OX40L costimulation in the absence of B7-1 and B7-2

Contact Info

Product

Resources

About

Commensal Bacteria Calibrate the Activation Threshold of Innate Antiviral Immunity

Cited by 857 publications

References 64 publications

Innate immune signaling and regulation in cancer immunotherapy

Innate immune signaling and regulation in cancer immunotherapy

Self‐priming determines high type I IFN production by plasmacytoid dendritic cells

Commensal microbes drive intestinal inflammation by IL-17–producing CD4 + T cells through ICOSL and OX40L costimulation in the absence of B7-1 and B7-2

Contact Info

Product

Resources

About

Commensal microbes drive intestinal inflammation by IL-17–producing CD4 ⁺ T cells through ICOSL and OX40L costimulation in the absence of B7-1 and B7-2