Conserved human effector Treg cell transcriptomic and epigenetic signature in arthritic joint inflammation

Mijnheer, Gerdien; Lutter, Lisanne; Mokrý, Michal; Wal, Marlot van der; Scholman, Rianne C.; Fleskens, Veerle; Pandit, Aridaman; Tao, Weiyang; Wekking, Mark; Vervoort, Stephin J.; Roberts, Ceri A.; Petrelli, Alessandra; Peeters, Janneke G. C.; Knijff, Marthe; Roock, Sytze de; Vastert, Sebastiaan J.; Taams, Leonie S.; Loosdregt, Jorg van; Wijk, Femke van

doi:10.1038/s41467-021-22975-7

Cited by 51 publications

(65 citation statements)

References 88 publications

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“…Transgenic mice with constitutively high-serum IL-6 have slightly increased levels of Treg cells with good suppressive function ( 44 ). A recent study described Treg perturbations in rheumatoid arthritis joints ( 45 ) that are reminiscent of those described here (in particular with elevated FoxP3 MFI), an interesting parallel since the arthritic joint is high in IL-6. It would have been valuable to assess Tregs from the lungs of COVID-19 patients directly, but such samples were not available to us.…”

Section: Discussionsupporting

confidence: 65%

Profound Treg perturbations correlate with COVID-19 severity

Galván-Peña

Léon

Chowdhary

et al. 2021

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

110

132

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The hallmark of severe COVID-19 is an uncontrolled inflammatory response, resulting from poorly understood immunological dysfunction. We hypothesized that perturbations in FoxP3+ T regulatory cells (Treg), key enforcers of immune homeostasis, contribute to COVID-19 pathology. Cytometric and transcriptomic profiling revealed a distinct Treg phenotype in severe COVID-19 patients, with an increase in Treg proportions and intracellular levels of the lineage-defining transcription factor FoxP3, correlating with poor outcomes. These Tregs showed a distinct transcriptional signature, with overexpression of several suppressive effectors, but also proinflammatory molecules like interleukin (IL)-32, and a striking similarity to tumor-infiltrating Tregs that suppress antitumor responses. Most marked during acute severe disease, these traits persisted somewhat in convalescent patients. A screen for candidate agents revealed that IL-6 and IL-18 may individually contribute different facets of these COVID-19–linked perturbations. These results suggest that Tregs may play nefarious roles in COVID-19, by suppressing antiviral T cell responses during the severe phase of the disease, and by a direct proinflammatory role.

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Section: Discussionsupporting

confidence: 65%

Profound Treg perturbations correlate with COVID-19 severity

Galván-Peña

Léon

Chowdhary

et al. 2021

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

110

132

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“…BATF is a known key driver in eTreg differentiation 7,19,20 , and indeed, our analysis revealed BATF as the primary local regulon for differentiation of Tregs that recently migrated to SF. RUNX1 and NFYC have also been previously associated with Treg development, maintenance and differentiation, and TBX21 is a possible driver of the Th1-associated co-transcriptional program 7,21,22 , whereas for example SP3 is associated with generic processes including proliferation, apoptosis and metabolism 23 . BHLHE40 was identified as a novel regulon for eTreg differentiation, and target genes mostly comprised cluster 4-associated genes including CXCL13, GPR56 and KLRB1 .…”

Section: Resultssupporting

confidence: 64%

“…Microenvironmental cues can shape the transcriptomic signature of Tregs with a resulting co-transcriptional Th-cell program 5,7 . These can be distinguished based on the expression pattern of the chemokine receptors CXCR3, CCR4, CCR6, CCR10 and CXCR5 15 .…”

Section: Resultsmentioning

confidence: 99%

Human regulatory T-cells locally differentiate and are functionally heterogeneous within the inflamed arthritic joint

Lutter

Wal

Brand

et al. 2022

Preprint

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Objective: Tregs are crucial for immune regulation, and environment-driven adaptation of effector (e)Tregs is essential for local functioning. However, the extent of human Treg heterogeneity in inflammatory settings is unclear. Methods: We combined single-cell RNA- and TCR-sequencing on Tregs derived from 4-6 patients with juvenile idiopathic arthritis (JIA) to investigate the functional heterogeneity of human synovial fluid (SF)-derived Tregs from inflamed joints. Confirmation and suppressive function of the identified Treg clusters was assessed by flow cytometry. Results: Four Treg clusters were identified; incoming, activated eTregs with either a dominant suppressive or cytotoxic profile, and GPR56+CD161+CXCL13+ Tregs. Pseudotime analysis showed differentiation towards either classical eTreg profiles or GPR56+CD161+CXCL13+ Tregs supported by TCR data. Despite its most differentiated phenotype GPR56+CD161+CXCL13+ Tregs were shown to be suppressive. Furthermore, BATF was identified as an overarching eTreg regulator, with the novel Treg-associated regulon BHLHE40 driving differentiation towards GPR56+CD161+CXCL13+ Tregs, and JAZF1 towards classical eTregs. Conclusion: Our study reveals a heterogeneous population of Tregs at the site of inflammation in JIA. SF Treg differentiate to a classical eTreg profile with a more dominant suppressive or cytotoxic profile that share a similar TCR repertoire, or towards GPR56+CD161+CXCL13+ Tregs with a more distinct TCR repertoire. Genes characterizing GPR56+CD161+CXCL13+ Tregs were also mirrored in other T-cell subsets in both the tumor and autoimmune setting. Finally, the identified key regulators driving SF Treg adaptation may be interesting targets for autoimmunity or tumor interventions.

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“…In contrast, other signaling events may stabilize Treg cell-type epigenetic patterns. Transcriptional and epigenetic analyses of human Treg cells from inflamed synovial joints compared with peripheral blood in pediatric patients revealed that Treg cells differentiate into effector Treg (eTreg) cells that are suppressive in vitro and display increased expression of core Treg cell genes ( 86 ). Importantly, epigenetic alterations in active enhancer marks, including H3K4me1 and H3K27ac, explained these transcriptional differences.…”

Section: Cytokine Signaling and The Epigenetics Of Treg Cell Plasticitymentioning

confidence: 99%

Epigenetic Control of Regulatory T Cell Stability and Function: Implications for Translation

2022

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FoxP3+ regulatory T (Treg) cells maintain immune homeostasis, promote self-tolerance, and have an emerging role in resolving acute inflammation, providing tissue protection, and repairing tissue damage. Some data suggest that FoxP3+ T cells are plastic, exhibiting susceptibility to losing their function in inflammatory cytokine-rich microenvironments and paradoxically contributing to inflammatory pathology. As a result, plasticity may represent a barrier to Treg cell immunotherapy. Here, we discuss controversies surrounding Treg cell plasticity and explore determinants of Treg cell stability in inflammatory microenvironments, focusing on epigenetic mechanisms that clinical protocols could leverage to enhance efficacy and limit toxicity of Treg cell-based therapeutics.

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Conserved human effector Treg cell transcriptomic and epigenetic signature in arthritic joint inflammation

Cited by 51 publications

References 88 publications

Profound Treg perturbations correlate with COVID-19 severity

Profound Treg perturbations correlate with COVID-19 severity

Human regulatory T-cells locally differentiate and are functionally heterogeneous within the inflamed arthritic joint

Epigenetic Control of Regulatory T Cell Stability and Function: Implications for Translation

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