Unlocking the Role of Exercise on CD4+ T Cell Plasticity

Goldsmith, Chloe D.; Donovan, Thomasina; Vlahovich, Nicole; Pyne, David B.

doi:10.3389/fimmu.2021.729366

Cited by 3 publications

(3 citation statements)

References 49 publications

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“…DNA cytosine modifications are known to be cell-type specific 1 , however the role of these modifications in Th cell identity is not well understood. The present study addressed the relationship between DNA methylation and Th cell identity, characterizing 5mC and 5hmC of murine CD4 Th cell subsets (Th0, Th1, Th2, Th17, Th17-noTGFβ and Tregs) by long read single molecule native DNA sequencing.…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, by characterizing methylation profiles in our identity gene panel, we were able to discriminate the unique Th17-noTGFβ cells ( Figure 2B ) indicating that an epigenetic approach has the potential to identify additional pathogenic and intermediate Th cell subsets. Emerging evidence suggests metabolomics and epigenetics work in concert to alter Th cell identity 1 . We have previously used this targeted sequencing approach to evaluate the relationship between metabolism and the epigenetic plasticity of regulatory T cells 4 .…”

Section: Discussionmentioning

confidence: 99%

“…In general, adaptive immunity in both protective and autoimmune settings is orchestrated by the emergence of polarized effector CD4 T helper (Th) lymphocyte subsets of specialized function. Naive CD4 Th0 cells under the influence of cytokines and TCR signaling can give rise to different effector cells including Th1,Th2, Th17, T regulatory (Treg) 1,2 . Furthermore, plasticity is an important property of Th cells, whereby they adapt their functions in response to a changing environment forming a continuum of polarized phenotypes 3 .…”

Section: Introductionmentioning

confidence: 99%

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Single molecule DNA methylation and hydroxymethylation reveal unique epigenetic identity profiles of T helper cells

Goldsmith

Fesneau

Thevin

et al. 2023

Preprint

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Both identity and plasticity of CD4 T helper (Th) cells are regulated in part by epigenetic mechanisms. However, a method that reliably and readily profiles DNA base modifications is still needed to finely study Th cell differentiation. Cytosine methylation (5mC) and cytosine hydroxymethylation (5hmC) are DNA modifications that identify stable cell phenotypes but their potential to characterize intermediate cell transitions has not yet been evaluated. To assess transition states in Th cells, we developed a new method to profile Th cell identity using cas9-targeted single molecule nanopore sequencing and found that 5mC and 5hmC can be used as markers of cellular identity. Targeting as few as 10 selected genomic loci, we were able to distinguish major differentiated T cell subtypes as well as intermediate phenotypes by their native DNA 5mC/5hmC patterns. Moreover, by using off-target sequences we were able to infer transcription factor activities relevant to each cell subtype. Our analysis demonstrates the importance of epigenetic regulation by 5mC and 5hmC modifications in the establishment of Th cell identity. Furthermore, our data highlight the potential to exploit this immune profiling application to elucidate the pathogenic role of Th transition states in autoimmune diseases.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Single molecule DNA methylation and hydroxymethylation reveal unique epigenetic identity profiles of T helper cells

Goldsmith

Fesneau

Thevin

et al. 2023

Preprint

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Respiratory and Metabolic Responses of CD4+ T Cells to Acute Exercise and Their Association with Cardiorespiratory Fitness

GEBHARDT,

HEBECKER,

HONEKAMP

et al. 2024

Medicine &Amp; Science in Sports &Amp; Exercise

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Introduction The study aimed to investigate to what extent acute endurance exercise, especially eccentric exercise and cardiorespiratory fitness affect the metabolic profile of CD4+ cells. Methods 15 male, healthy adults aged between 20 and 33 years with a maximal oxygen uptake (VO2max) between 44 and 63 ml/kg/min performed a downhill run (DR) and a level run (LR) for 45 minutes at 70% of their VO2max on a treadmill in a cross-over design. Blood samples were taken before (T0), directly after (T1), 3 hours after (T3), and 24 hours (T24) after each exercise for analyzing leukocyte numbers and cytokine levels. Isolated CD4+ cells were incubated for 4 hours in autologous resting versus 3 hours after exercise serum (T3 DR and T3 LR), and subsequently, cellular respiration, transcriptomic, and metabolomics profiles were measured. Results The systemic immune inflammation index increased significantly after DR and LR at T1 and T3 (p < .001). In contrast, the transcriptomic and metabolic profile of CD4+ cells showed no significant alterations after incubation in T3 exercise serum. However, cardiorespiratory fitness positively correlated with the maximal mitochondrial respiration in CD4+ cells after incubation with T3 LR serum (r = .617, p = .033) and with gene expression of oxidative phosphorylation and levels of different metabolites. Similarly, VO2max was associated with an anti-inflammatory profile on RNA level. Lower lactate, methylmalonic acid, and D-gluconic acid levels were found in CD4+ cells of participants with a high VO2max (p < .001). Conclusions Acute exercise leads to a mild pro-inflammatory milieu with only small changes in the metabolic homeostasis of CD4+ cells. High cardiorespiratory fitness is associated with a metabolic shift to oxidative phosphorylation in CD4+ cells. Functional relevance of this metabolic shift needs to be further investigated.

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Single-Molecule DNA Methylation Reveals Unique Epigenetic Identity Profiles of T Helper Cells

Goldsmith,

Thevin,

Fesneau

et al. 2024

The Journal of Immunology

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Both identity and plasticity of CD4 T helper (Th) cells are regulated in part by epigenetic mechanisms. However, a method that reliably and readily profiles DNA base modifications is still needed to finely study Th cell differentiation. Cytosine methylation in CpG context (5mCpG) and cytosine hydroxymethylation (5hmCpG) are DNA modifications that identify stable cell phenotypes, but their potential to characterize intermediate cell transitions has not yet been evaluated. To assess transition states in Th cells, we developed a method to profile Th cell identity using Cas9-targeted single-molecule nanopore sequencing. Targeting as few as 10 selected genomic loci, we were able to distinguish major in vitro polarized murine T cell subtypes, as well as intermediate phenotypes, by their native DNA 5mCpG patterns. Moreover, by using off-target sequences, we were able to infer transcription factor activities relevant to each cell subtype. Detection of 5mCpG and 5hmCpG was validated on intestinal Th17 cells escaping transforming growth factor β control, using single-molecule adaptive sampling. A total of 21 differentially methylated regions mapping to the 10-gene panel were identified in pathogenic Th17 cells relative to their nonpathogenic counterpart. Hence, our data highlight the potential to exploit native DNA methylation profiling to study physiological and pathological transition states of Th cells.

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Unlocking the Role of Exercise on CD4+ T Cell Plasticity

Cited by 3 publications

References 49 publications

Single molecule DNA methylation and hydroxymethylation reveal unique epigenetic identity profiles of T helper cells

Single molecule DNA methylation and hydroxymethylation reveal unique epigenetic identity profiles of T helper cells

Respiratory and Metabolic Responses of CD4+ T Cells to Acute Exercise and Their Association with Cardiorespiratory Fitness

Single-Molecule DNA Methylation Reveals Unique Epigenetic Identity Profiles of T Helper Cells

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