Single‐cell technologies to study the immune system

Proserpio, Valentina; Mahata, Bidesh

doi:10.1111/imm.12553

Cited by 55 publications

(33 citation statements)

References 64 publications

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“…Single-cell transcriptomics has provided detailed pictures of cellular heterogeneity related to disease pathology (55), in which Th17 cells exhibit a range of phenotypes from pathogenic to regulatory in nature (56,57). Our single-cell transcriptomics data indeed show significant T cell heterogeneity, with a consistent set of phenotypes that correlate with subsets of highly inflammatory memory and resting cells.…”

Section: Discussionmentioning

confidence: 61%

Histone H3K27me3 demethylases regulate human Th17 cell development and effector functions by impacting on metabolism

Cribbs

Terlecki-Zaniewicz

Philpott

et al. 2020

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

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Section: Discussionmentioning

confidence: 61%

Histone H3K27me3 demethylases regulate human Th17 cell development and effector functions by impacting on metabolism

Cribbs

Terlecki-Zaniewicz

Philpott

et al. 2020

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

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“…Single-cell transcriptomics has provided detailed pictures of cellular heterogeneity related to disease pathology (52), in which Th17 cells exhibits a range of phenotypes from pathogenic to regulatory in nature (53, 54). Our single-cell transcriptomics data indeed show significant T-cell heterogeneity, with a consistent set of phenotypes that correlate with subsets of highly inflammatory, memory and resting cells.…”

Section: Discussionmentioning

confidence: 99%

Histone H3K27me3 demethylases regulate human Th17 cell development and effector functions by impacting on metabolism

Cribbs

Terlecki-Zaniewicz

Philpott

et al. 2019

Preprint

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C r i b b s e t a l 2 SIGNIFICANCE STATEMENTThe precise regulation of Th17 cell metabolic function is central to an inflammatory response.Following activation, T cells undergo metabolic reprogramming and utilise up-regulated glycolysis to increase the availability of ATP. This work establishes an epigenetic link between the H3K27 demethylases KDM6A/B and the coordination of a metabolic response in activated Th17 cells.Inhibition of KDM6A/B leads to global increases in the repressive H3K27me3 histone mark resulting in down-regulation of key transcription factors, followed by metabolic reprogramming and the induction of anergy in Th17 cells. This work suggests a critical role of KDM6 enzymes in maintaining Th17 functions by controlling metabolic switches, necessary for T cells to adapt to their specific roles. C r i b b s e t a l 3 ABSTRACT T helper (T h ) cells are CD4+ effector T cells that play an instrumental role in immunity by shaping the inflammatory cytokine environment in a variety of physiological and pathological situations. Using a combined chemico-genetic approach we identify histone H3K27 demethylases KDM6A and KDM6B as central regulators of human Th subsets. The prototypic KDM6 inhibitor GSK-J4 increases genome-wide levels of the repressive H3K27me3 chromatin mark and leads to suppression of the key transcription factor RORγt during Th17 differentiation, whereas in mature Th17 cells an altered transcriptional program leads to a profound metabolic reprogramming with concomitant suppression of IL-17 cytokine levels and reduced proliferation. Single cell analysis reveals a specific shift from highly inflammatory cell subsets towards a resting state upon demethylase inhibition. The apparent root cause of the observed anti-inflammatory phenotype in stimulated Th17 cells is reduced expression of key metabolic transcription factors, such as PPRC1 and c-myc. Overall, this leads to reduced mitochondrial biogenesis resulting in a metabolic switch with concomitant anti-inflammatory effects. These data are consistent with an opposing effect of GSK-J4 on Th17 T-cell differentiation pathways directly related to proliferation and effector cytokine profiles.

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“…In the process of gaining a deeper understanding of how the different CD4+ve Th subsets are induced to protect against different infections, it has become clear that they are no longer considered to be mutually-exclusive or irreversibly committed, but demonstrate a degree of plasticity and cross-regulation (reviewed by Zhu et al [3]). Single-cell technologies are providing further insights into T cell biology and regulation of immune responses [37] which underpins novel strategic approaches to disease control and vaccine design.…”

Section: Discussionmentioning

confidence: 99%

Enhancing the toolbox to study IL-17A in cattle and sheep

Wattegedera

Corripio-Miyar

Pang

et al. 2017

Vet Res

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The development of methods to detect cytokine expression by T cell subsets in ruminants is fundamental to strategic development of new livestock vaccines for prevention of infectious diseases. It has been possible to detect T cell expression of IFN-γ, IL-4 and IL-10 in ruminants for many years but methods to detect expression of IL-17A are relatively limited. To address this gap in capability we have cloned bovine and ovine IL-17A cDNAs and expressed biologically-active recombinant proteins in Chinese Hamster Ovary (CHO) cells. We used the transfected CHO cells to screen commercially-available antibodies for their ability to detect IL-17A expression intracellularly and in culture supernates. We demonstrate that an ELISA for bovine IL-17A detects native ovine IL-17A. Moreover, the constituent polyclonal antibodies (pabs) in the ELISA were used to enumerate peripheral blood mononuclear cells (PBMC) expressing IL-17A from cattle and sheep by ELISpot. We identified two monoclonal antibodies (mabs) that detect recombinant intracellular IL-17A in CHO cells by flow cytometry. One of these mabs was used to detect native intracellular IL-17A expression in PBMC in conjunction with cell surface phenotyping mabs [CD4+ve, CD8+ve and Workshop Cluster 1 (WC-1)+ve gamma-delta (γδ)] we show that distinct T cell subsets in cattle (defined as CD4+ve, CD8+ve or WC-1+ve) and sheep (defined as CD4+ve or WC-1+ve) can express IL-17A following activation. These novel techniques provide a solid basis to investigate IL-17A expression and define specific CD4+ve T cell subset activation in ruminants.Electronic supplementary materialThe online version of this article (doi:10.1186/s13567-017-0426-5) contains supplementary material, which is available to authorized users.

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Single‐cell technologies to study the immune system

Cited by 55 publications

References 64 publications

Histone H3K27me3 demethylases regulate human Th17 cell development and effector functions by impacting on metabolism

Histone H3K27me3 demethylases regulate human Th17 cell development and effector functions by impacting on metabolism

Histone H3K27me3 demethylases regulate human Th17 cell development and effector functions by impacting on metabolism

Enhancing the toolbox to study IL-17A in cattle and sheep

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