Multidimensional assessment of alveolar T cells in critically ill patients

Walter, James M.; Helmin, Kathryn A.; Abdala‐Valencia, Hiam; Wunderink, Richard G.; Singer, Benjamin D.

doi:10.1172/jci.insight.123287

Cited by 59 publications

(86 citation statements)

References 21 publications

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“…Measurement and analysis of DNA methylation was performed as previously described (McGrath-Morrow et al, 2018;Singer, 2019;Walter et al, 2018;Wang et al, 2018;Weinberg et al, 2019). Briefly, genomic DNA was isolated from sorted macrophage populations (Qiagen AllPrep Micro kit).…”

Section: Modified Reduced Representation Bisulfite Sequencingmentioning

confidence: 99%

The Aging Microenvironment Shapes Alveolar Macrophage Identity in Aging

McQuattie‐Pimentel¹,

Ren²,

Joshi³

et al. 2019

Preprint

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A dysfunctional response to inhaled pathogens and toxins drives a substantial portion of the susceptibility to acute and chronic lung disease in the elderly. We used transcriptomic profiling combined with genetic lineage tracing, heterochronic adoptive transfer, parabiosis and treatment with metformin to show that the lung microenvironment defines the phenotype of long-lived alveolar macrophages during aging. While tissue-resident alveolar macrophages persist in the lung without input from monocytes over the lifespan, severe lung injury results in their replacement with monocyte-derived alveolar macrophages. These monocyte-derived alveolar macrophages are also shaped by the microenvironment both during aging and in response to a subsequent environmental challenge to become transcriptionally and functionally similar to tissue-resident alveolar macrophages. These findings show that changes in alveolar macrophage phenotypes during injury and aging are not cell autonomous but instead are shaped by changes in the aging lung microenvironment.

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Section: Modified Reduced Representation Bisulfite Sequencingmentioning

confidence: 99%

The Aging Microenvironment Shapes Alveolar Macrophage Identity in Aging

McQuattie‐Pimentel¹,

Ren²,

Joshi³

et al. 2019

Preprint

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“…Modified reduced representation bisulfite sequencing. Genomic DNA was subjected to mRRBS as previously described (46,54,(59)(60)(61)(62). Bisulfite conversion efficiency averaged 99.52% ± 0.052% (SD) as estimated by the measured frequency of unmethylated CpGs in λ-bacteriophage DNA (New England BioLabs, #N3013S) added at a 1:200 mass ratio to each sample.…”

Section: Discussionmentioning

confidence: 99%

“…Phenotype ontology (45) with the basal+extension association rule (constitutive 5 kb upstream and 1 kb downstream, up to 1000 kb max extension) against the whole genome as background. Metagene analysis was performed using SeqMonk's quantitation trend plot function across Treg cell-specific super-enhancer elements (19) after liftover of coordinates from the mm9 to the mm10 reference genome (59).…”

Section: Functional Enrichment Analysis Was Performed Using the Greatmentioning

confidence: 99%

“…experiments. For next-generation sequencing experiments, indicated sample sizes were chosen to obtain a minimum of 10 6 unique CpGs per biological replicate as modeled using the DSS statistical procedures (46,54,(59)(60)(61)(62). Computational analysis was performed using Genomics Nodes and Analytics Nodes on Quest, Northwestern University's High-Performance Computing Cluster.…”

Section: Functional Enrichment Analysis Was Performed Using the Greatmentioning

confidence: 99%

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Maintenance DNA methylation is essential for regulatory T cell development and stability of suppressive function

Helmin¹,

Morales‐Nebreda²,

Acosta³

et al. 2020

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Regulatory T (Treg) cells require Foxp3 expression and induction of a specific DNA hypomethylation signature during development, after which Treg cells persist as a self-renewing population that regulates immune system activation. Whether maintenance DNA methylation is required for Treg cell lineage development and stability and how methylation patterns are maintained during lineage self-renewal remain unclear. Here, we demonstrate that the epigenetic regulator Uhrf1 is essential for maintenance of methyl-DNA marks that stabilize Treg cellular identity by repressing effector T cell transcriptional programs. Constitutive and induced deficiency of Uhrf1 within Foxp3 + cells resulted in global yet non-uniform loss of DNA methylation, derepression of inflammatory transcriptional programs, destabilization of the Treg cell lineage, spontaneous inflammation, and enhanced tumor immunity. These findings support a paradigm in which maintenance DNA methylation is required in distinct regions of the Treg cell genome for both lineage establishment and stability of identity and suppressive function.

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“…Foxp3 dampen inflammatory responses to both endogenous and exogenous antigens. Aside from their role in maintaining immune homeostasis through their capacity to suppress over-exuberant immune system activation, Treg cells reside in healthy tissues and accumulate in the lung in response to viral injury to promote tissue repair (5,6). Our group and others have shown that in murine models of lung injury, Treg cells are master orchestrators of recovery (7)(8)(9)(10).…”

Section: Immunomodulatory Regulatory T (Treg) Cells Expressing the LImentioning

confidence: 99%

Aging imparts cell-autonomous dysfunction to regulatory T cells during recovery from influenza pneumonia

Morales‐Nebreda¹,

Helmin²,

Markov³

et al. 2020

Preprint

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Regulatory T (Treg) cells orchestrate resolution and repair of acute lung inflammation and injury following viral pneumonia. Compared with younger patients, older individuals experience impaired recovery and worse clinical outcomes after severe viral infections, including influenza and the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Whether age is a key determinant of Treg cell pro-repair function following lung injury remains unknown. Here, we show that aging results in a cell-autonomous impairment of reparative Treg cell function following experimental influenza pneumonia. Transcriptional and DNA methylation profiling of sorted Treg cells provide insight into the mechanisms underlying their age-related dysfunction, with Treg cells from aged mice demonstrating both loss of reparative programs and gain of maladaptive programs. Novel strategies that restore youthful Treg cell functional programs could be leveraged as therapies to improve outcomes among older individuals with severe viral pneumonia.

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Multidimensional assessment of alveolar T cells in critically ill patients

Cited by 59 publications

References 21 publications

The Aging Microenvironment Shapes Alveolar Macrophage Identity in Aging

The Aging Microenvironment Shapes Alveolar Macrophage Identity in Aging

Maintenance DNA methylation is essential for regulatory T cell development and stability of suppressive function

Aging imparts cell-autonomous dysfunction to regulatory T cells during recovery from influenza pneumonia

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