Dynamic changes in the regulatory T cell heterogeneity and function by murine IL-2 mutein

Lu, Daniel; Wu, Hao; Driver, Ian; Ingersoll, Sarah; Sohn, Sue J.; Wang, Songli; Phee, Hyewon

doi:10.1101/669978

Cited by 3 publications

(4 citation statements)

References 81 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Subsequent scRNA-seq studies found a similar population of ISG-Tregs in the spleen (∼5%) (data not shown). This population of Tregs is similar to one identified in the spleen, lung, gut, and skin at steady state and following treatment with IL-2 mutein (Lu et al, 2020; Miragaia et al, 2019). Thus, the percentage of Tregs labeled in Mx1-Cre x Foxp3-iDTR mice closely mimics that detected in the spleen and thymus by scRNA-seq.…”

Section: Resultssupporting

confidence: 61%

“…Mice bearing Tregs that are deficient in these transcription factors develop uncontrolled inflammation in multiple contexts (Chaudhry et al, 2009; Harrison et al, 2019; Levine et al, 2017; Wohlfert et al, 2011). More recently, single-cell RNA-sequencing (scRNA-seq) studies have allowed the examination of Treg heterogeneity in more depth (Lu et al, 2020; Miragaia et al, 2019; Owen et al, 2022; Owen et al, 2019). These studies demonstrated transcriptional heterogeneity in Tregs within the spleen, lymph nodes, thymus, lung and colon at steady-state, and that Tregs undergo a step-wise acquisition of a tissue-like transcriptome as they move from the lymph nodes to the tissue itself (Delacher et al, 2020; Miragaia et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Influenza infection recruits distinct waves of regulatory T cells to the lung that limit lung resident IgA+ B cells

Sjaastad

Owen

Joo

et al. 2022

Preprint

View full text Add to dashboard Cite

The role of regulatory T cells (Tregs) in limiting responses to pathogens in tissues remains poorly described. We used scRNA-Seq and a newly generated Foxp3-lineage reporter line (Foxp3-iDTR mice) to track Tregs in the lungs and peripheral blood following infection with influenza virus. Few Tregs of any type were found in the lung at steady-state. Following influenza infection Tregs expressing a strong interferon-stimulated gene signature (ISG-Tregs) appeared by day 3, peaked by day 7, and largely disappeared by day 21 post-infection. A second diverse wave of tissue-repair-like Tregs (TR-Tregs) appeared by day 10 and were maintained through day 21 post-infection. These two distinct Treg subsets had different gene expression patterns and distinct TCR repertoires. To establish the role of Tregs during influenza infection, we acutely ablated Tregs at day 6 post-infection; this resulted in a significant increase in IgA+ B cells in the lung. To determine whether distinct Tregs subsets could also be observed in response to respiratory viral infections in humans we analyzed scRNA-Seq datasets of patients with COVID-19. Peripheral blood from healthy human volunteers had multiple Treg subsets defined by unique gene expression patterns, but few ISG-Tregs. In contrast, two distinct Tregs subsets were expanded in COVID-19 patients - ISG-Tregs and IL32 expressing Tregs (16-fold and 2-fold increased, respectively). ISG-Tregs were present at significantly higher levels in patients with mild versus severe COVID-19, while IL32 expressing Tregs showed the opposite pattern. Thus, the Treg response to respiratory viruses in humans is also diverse and correlates with disease outcome.

show abstract

Section: Resultssupporting

confidence: 61%

Section: Introductionmentioning

confidence: 99%

Influenza infection recruits distinct waves of regulatory T cells to the lung that limit lung resident IgA+ B cells

Sjaastad

Owen

Joo

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Notably, our results revealed that the higher variance in the detection of lowly expressed transcripts commonly observed in techniques with lower sensitivity is not necessarily overcome by pooling across single cells when performing pseudo-bulk analyses. Strengthening the underlying mRNA detection sensitivity can improve downstream analyses to identify marker genes as well as classify subtle immune subtypes and cell states with small, but significant differences in gene expression, and can facilitate the identification of novel immune subpopulations [31].…”

Section: Discussionmentioning

confidence: 99%

Systematic comparison of high-throughput single-cell RNA-seq methods for immune cell profiling

Yamawaki

Ellwanger

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

Background: Elucidation of immune populations with single-cell RNA-seq has greatly benefited the field of immunology by deepening the characterization of immune heterogeneity and leading to the discovery of new subtypes. However, single-cell methods inherently suffer from limitations in the recovery of complete transcriptomes due to the prevalence of cellular and transcriptional dropout events. This issue is often compounded by limited sample availability and limited prior knowledge of heterogeneity, which can confound data interpretation. Results: Here, we systematically benchmarked seven high-throughput single-cell RNA-seq methods. We prepared 21 libraries under identical conditions of a defined mixture of two human and two murine lymphocyte cell lines, simulating heterogeneity across immune-cell types and cell sizes. We evaluate methods by their cell recovery rate, library efficiency, sensitivity, and ability to recover expression signatures for each cell type. We observed higher mRNA detection sensitivity with the 10x Genomics 5’ v1 and 3’ v3 methods. We demonstrate that these methods have fewer drop-out events which facilitates the identification of differentially-expressed genes and improves the concordance of single-cell profiles to immune bulk RNA-seq signatures.Conclusion: Overall, our characterization of immune cell mixtures provides useful metrics, which can guide selection of a high-throughput single-cell RNA-seq method for profiling more complex immune-cell heterogeneity usually found in vivo.

show abstract

“…Similarly, the use of IL-2-anti-IL-2 complexes to target IL-2 specifically to CD25 preferentially expands Treg cells [33,113]. These findings led to the development of IL-2 muteins, in which IL-2 is both targeted and stabilized, enhancing Treg cell expansion in vivo [114][115][116]. Additional promising approaches to promote and expand Treg cells in vivo include in vivo delivery of rapamycin or TNFR2 agonists.…”

Section: In Vivo Treg Cell Expansion and Transfermentioning

confidence: 99%

Regulatory T cells as a therapeutic approach for inflammatory bowel disease

Lauková

Zaretsky

2023

Eur J Immunol

View full text Add to dashboard Cite

Foxp3 + T regulatory (Treg) cells suppress inflammation and are essential for maintaining tissue homeostasis. A growing appreciation of tissue-specific Treg functions has built interest in leveraging the endogenous suppressive mechanisms of these cells into cellular therapeutics in organ-specific diseases. Notably, Treg cells play a critical role in maintaining the intestinal environment. As a barrier site, the gut requires Treg cells to mediate interactions with the microbiota, support barrier integrity, and regulate the immune system. Without fully functional Treg cells, intestinal inflammation and microbial dysbiosis ensue. Thus, there is a particular interest in developing Treg cellular therapies for intestinal inflammatory disease, such as inflammatory bowel disease (IBD). This article reviews some of the critical pathways that are dysregulated in IBD, Treg cell mechanisms of suppression, and the efforts and approaches in the field to develop these cells as a cellular therapy for IBD.

show abstract

Dynamic changes in the regulatory T cell heterogeneity and function by murine IL-2 mutein

Cited by 3 publications

References 81 publications

Influenza infection recruits distinct waves of regulatory T cells to the lung that limit lung resident IgA+ B cells

Influenza infection recruits distinct waves of regulatory T cells to the lung that limit lung resident IgA+ B cells

Systematic comparison of high-throughput single-cell RNA-seq methods for immune cell profiling

Regulatory T cells as a therapeutic approach for inflammatory bowel disease

Contact Info

Product

Resources

About