A Novel Model for IFN-γ–Mediated Autoinflammatory Syndromes

Reinhardt, R. Lee; Liang, Hong-Erh; Bao, Katherine; Price, April; Mohrs, Markus; Kelly, Ben L.; Locksley, Richard M.

doi:10.4049/jimmunol.1401992

Cited by 66 publications

(62 citation statements)

References 55 publications

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“…To assess effects of endogenous IFN-γ on ILC2 function, we used Yeti mice (Stetson et al, 2003), in which the 3′ untranslated region (UTR) of IFN-γ is stabilized by a YFP-bovine growth hormone poly-A construct, leading to constitutive increases in IFN-γ; heterozygous mice were used here, thus avoiding overt IFN-γ-induced auto-inflammation (Reinhardt et al, 2015). Similar to wild-type mice on high-fat diet (Molofsky et al, 2013), young heterozygous Yeti mice on normal diet have fewer total adipose tissue ILC2, eosinophils and Treg cells, show attenuated IL-5 and ICOSL expression by ILC2 and rare Th2 cells, and accumulate NK cells, Th1 CD4 + T cells and CD8 + T cells (Figure 6E–I, Figure S6H, and data not shown).…”

Section: Resultsmentioning

confidence: 99%

Interleukin-33 and Interferon-γ Counter-Regulate Group 2 Innate Lymphoid Cell Activation during Immune Perturbation

et al. 2015

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SUMMARY Group 2 innate lymphoid cells (ILC2) and regulatory T (Treg) cells are systemically induced by helminth infection but also sustain metabolic homeostasis in adipose tissue and contribute to tissue repair during injury. Here we show interleukin-33 (IL-33) mediates activation of ILC2 and Treg cells in resting adipose tissue, but also after helminth infection or treatment with IL-2. Unexpectedly, ILC2-intrinsic IL-33 activation was required for Treg cell accumulation in vivo, and was independent of ILC2 type 2 cytokines but partially dependent on direct co-stimulatory interactions via ICOSL-ICOS. IFN-γ inhibited ILC2 activation and Treg cell accumulation by IL-33 in infected tissue as well as adipose tissue, where repression increased with aging and high-fat diet-induced obesity. IL-33 and ILC2 are central mediators of type 2 immune responses that promote tissue and metabolic homeostasis, and IFN-γ suppresses this pathway, likely to promote inflammatory responses and divert metabolic resources necessary to protect the host.

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Section: Resultsmentioning

confidence: 99%

Interleukin-33 and Interferon-γ Counter-Regulate Group 2 Innate Lymphoid Cell Activation during Immune Perturbation

et al. 2015

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“…To do this we used an IFN-gamma cytokine reporter strain ( Ifnγ Great ) to assess cytokine production. Ifnγ Great reporter mice utilize a bicistronic reporter to generate both IFN-gamma and yellow fluorescent protein (YFP) expression from the same transcript (3, 38). In these mice, cells that produce IFN-gamma concomitantly express YFP.…”

Section: Resultsmentioning

confidence: 99%

BATF Modulates the Th2 Locus Control Region and Regulates CD4+ T Cell Fate during Antihelminth Immunity

Bao

Carr

et al. 2016

The Journal of Immunology

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The AP-1 factor, basic leucine zipper transcription factor, ATF-like (BATF) is important for CD4+ T-helper (Th) 17, Th9 and follicular T helper (Tfh) cell development. However, its precise role in Th2 differentiation and function remains unclear, and the necessity of BATF in non-allergic settings of type-2 immunity has not been explored. Here, we show that in response to parasitic helminths, Batf−/− mice are unable to generate both Tfh and Th2 cells. As a consequence, Batf−/− mice fail to establish productive type-2 immunity during primary and secondary infection. Batf−/− CD4+ T cells do not achieve type-2 cytokine competency, which implies that BATF plays a key role in the regulation of interleukin(IL)-4 and IL-13. In contrast to Th17 and Th9 cell subsets where BATF binds directly to promoter and enhancer regions to regulate cytokine expression, our results show that BATF is significantly enriched at Rad50 hypersensitivity sites (RHS) 6 and 7 of the locus control region (LCR) relative to AP-1 sites surrounding type-2 cytokine loci in Th2 cells. Indeed, Batf−/− CD4+ T cells do not obtain permissive epigenetic modifications within the Th2 locus, which have been linked to RHS6 and RHS7 function. In sum, these findings reveal BATF as a central modulator of peripheral and humoral hallmarks of type-2 immunity, and begin to elucidate a novel mechanism by which BATF regulates type-2 cytokine production through its modification of the Th2 LCR.

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“…DPE-GFP mice (21) were generously provided by Ulrich von Andrian (Dept. of Microbiology and Immunobiology, Harvard Medical School), IFN-γ reporter with endogenous polyA tail (GREAT) mice (22) were kindly provided by Andrew Luster (Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital). Tumor growth was monitored by caliper measurement and the area (A) of these predominantly two-dimensional tumors was calculated using the formula A = length * width.…”

Section: Methodsmentioning

confidence: 99%

In vivo imaging reveals a tumor-associated macrophage–mediated resistance pathway in anti–PD-1 therapy

et al. 2017

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Monoclonal antibodies targeting the immune checkpoint Programmed Death-1 (aPD-1 mAbs) have demonstrated impressive benefits for the treatment of some cancers; yet, these drugs are not always effective and we still have a limited understanding of the mechanisms that contribute to their efficacy or lack thereof. Here we employed in vivo imaging to uncover the fate and activity of aPD-1 mAbs in real-time and at subcellular resolution in mice. We show that aPD-1 mAbs effectively bind PD-1+ tumor-infiltrating CD8+ T cells at early time-points after administration. However, this engagement is transient, as aPD-1 mAbs are captured within minutes from the T cell surface by PD-1− tumor-associated macrophages. We further show that macrophage accrual of aPD-1 mAbs depends both on the drug’s Fc domain glycan and on Fcγ-receptors (FcγRs) expressed by host myeloid cells, and extend these findings to the human setting. Finally, we demonstrate that in vivo blockade of FcγRs prior to aPD-1 mAb administration substantially prolongs aPD-1 mAb binding to tumor-infiltrating CD8+ T cells and enhances immunotherapy-induced tumor regression in mice. These investigations yield new insight into aPD-1 target engagement in vivo and identify specific Fc : FcγR interactions that can be modulated to improve checkpoint blockade therapy.

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A Novel Model for IFN-γ–Mediated Autoinflammatory Syndromes

Cited by 66 publications

References 55 publications

Interleukin-33 and Interferon-γ Counter-Regulate Group 2 Innate Lymphoid Cell Activation during Immune Perturbation

Interleukin-33 and Interferon-γ Counter-Regulate Group 2 Innate Lymphoid Cell Activation during Immune Perturbation

BATF Modulates the Th2 Locus Control Region and Regulates CD4+ T Cell Fate during Antihelminth Immunity

In vivo imaging reveals a tumor-associated macrophage–mediated resistance pathway in anti–PD-1 therapy

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