Charles R. Roll

University of Minnesota Medical Center

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Co-Authors

Troy R. Torgerson

Allen Institute for Immunology

Julian Reading

Allen Institute for Immunology

Alexander T. Heubeck

Allen Institute for Immunology

Thomas F. Bumol

Allen Institute for Immunology

Peter J. Skene

Allen Institute for Immunology

Veronica Hernandez

Allen Institute for Immunology

Morgan Weiss

Allen Institute for Immunology

Zachary Thomson

Allen Institute for Immunology

Palak C. Genge

Allen Institute for Immunology

Katherine Henderson

Allen Institute for Immunology

Cooperative Institutions

Allen Institute for Immunology

Seattle University

University of Colorado Anschutz Medical Campus

University of Washington

Fred Hutch Cancer Center

University of Colorado Denver

Cape Town HVTN Immunology Laboratory / Hutchinson Centre Research Institute of South Africa

Cancer Research Center

University of California, San Diego

University of Minnesota Medical Center

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Author Correction: Trimodal single-cell profiling reveals a novel pediatric CD8αα+ T cell subset and broad age-related molecular reprogramming across the T cell compartment

Nature Immunology (2024)

Zachary Thomson Ziyuan He Elliott Swanson Katherine Henderson Cole Phalen

Reprogramming

Compartment (ship)

Profiling (computer programming)

Single-Cell Analysis

10.1038/s41590-024-01757-5

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Citations (0)

Tri-modal single cell (TEA-seq) profiling reveals a novel, epigenetically distinct T cell subset in children and global molecular reprogramming across age

The Journal of Immunology (2023)

Claire E. Gustafson Zachary Thomson Ziyuan He Elliot Swanson Katherine Henderson

Abstract Most single cell analyses of human T cell heterogeneity use a single modality (i.e., RNA or ATAC or protein), with limited ability to deconvolute complex cellular and molecular alterations that can occur during human aging and disease. Here, we use a new trimodal single cell technology (TEA-seq) to elucidate the interplay between the surface proteome, transcriptome, and epigenome in more than 300,000 T cells from healthy children (11–13 yrs) and older adults (55–65 yrs). We uncover that age universally drives molecular reprogramming across all T cell subsets towards a more activated basal state. Naive CD4 T cells, considered relatively resistant to aging, exhibited far more pronounced transcriptional reprogramming than naive CD8 T cells, in which alterations are preferentially driven by compositional shifts in naive-like memory subsets. We further discover a novel naïve-like CD8aa T cell subset lost with age that displays an innate-like transcriptome, a KLF/SP-rich epigenome and high IL-21 receptor expression. These data reveal the complex molecular landscape of the human T cell compartment that may contribute to differential immune responses across age. Supported by grants from NIH (K01 AG068373 to CEG) and the Allen Institute

Epigenome

Reprogramming

Mass cytometry

Proteome

10.4049/jimmunol.210.supp.249.07

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Phages Bind to Vegetative and Spore Forms of Paenibacillus larvae and to Vegetative Brevibacillus laterosporus

Frontiers in Microbiology (2021)

Thomas Brady Charles R. Roll Jamison K. Walker Christopher P. Fajardo Donald P. Breakwell

Paenibacillus larvae is the causative agent of American Foulbrood (AFB), the most destructive bacterial infection in honeybees. Even antibiotic-sensitive strains of P. larvae can produce recurrent AFB months to weeks post-antibiotic treatment due to the survival of bacterial spores. Recently, phages that infect P. larvae have been shown to effectively combat AFB in the field. Here, we present evidence that phages not only bind to vegetative P. larvae but also bind to P. larvae spores. Spore binding was observed in the results of three specific experiments: (1) bacteria counted by flow cytometry generated quantitative data of FITC-labeled phages that were bound to vegetative bacteria as well as those bound to spores, (2) electron microscopy captured images of phages bound to the surface of spores in both horizontal and vertical positions, and (3) phages incubated with P. larvae spores bound to the spores and created plaques in vegetative bacteria under conditions not conducive to spore activation, indicating that binding to spores is reversible and that the phages are still active. Identification of phages with reversible spore-binding capability for use in phage therapy may improve treatment of sporulating bacterial infections.

American foulbrood

10.3389/fmicb.2021.588035

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Citations (7)

Longitudinal Multi-omic Immune Profiling Reveals Age-Related Immune Cell Dynamics in Healthy Adults

bioRxiv (Cold Spring Harbor Laboratory) (2024)

Qiuyu Gong Mehul Sharma Emma L. Kuan Marla C. Glass Aishwarya Chander

The generation and maintenance of protective immunity is a dynamic interplay between host and environment that is impacted by age. Understanding fundamental changes in the healthy immune system that occur over a lifespan is critical in developing interventions for age-related susceptibility to infections and diseases. Here, we use multi-omic profiling (scRNA-seq, proteomics, flow cytometry) to examined human peripheral immunity in over 300 healthy adults, with 96 young and older adults followed over two years with yearly vaccination. The resulting resource includes scRNA-seq datasets of >16 million PBMCs, interrogating 71 immune cell subsets from our new Immune Health Atlas. This study allows unique insights into the composition and transcriptional state of immune cells at homeostasis, with vaccine perturbation, and across age. We find that T cells specifically accumulate age-related transcriptional changes more than other immune cells, independent from inflammation and chronic perturbation. Moreover, impaired memory B cell responses to vaccination are linked to a Th2-like state shift in older adults' memory CD4 T cells, revealing possible mechanisms of immune dysregulation during healthy human aging. This extensive resource is provided with a suite of exploration tools at https://apps.allenimmunology.org/aifi/insights/dynamics-imm-health-age/ to enhance data accessibility and further the understanding of immune health across age.

Profiling (computer programming)

Omics

10.1101/2024.09.10.612119

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Citations (4)

Longitudinal immune dynamics of mild COVID-19 define signatures of recovery and persistence

bioRxiv (Cold Spring Harbor Laboratory) (2021)

Aarthi Talla Suhas Vasaikar Maria P. Lemos Zoe Moodie Mark-Phillip Pebworth

SARS-CoV-2 has infected over 200 million and caused more than 4 million deaths to date. Most individuals (>80%) have mild symptoms and recover in the outpatient setting, but detailed studies of immune responses have focused primarily on moderate to severe COVID-19. We deeply profiled the longitudinal immune response in individuals with mild COVID-19 beginning with early time points post-infection (1-15 days) and proceeding through convalescence to >100 days after symptom onset. We correlated data from single cell analyses of peripheral blood cells, serum proteomics, virus-specific cellular and humoral immune responses, and clinical metadata. Acute infection was characterized by vigorous coordinated innate and adaptive immune activation that differed in character by age (young vs. old). We then characterized signals associated with recovery and convalescence to define and validate a new signature of inflammatory cytokines, gene expression, and chromatin accessibility that persists in individuals with post-acute sequelae of SARS-CoV-2 infection (PASC).

Convalescence

Persistence (discontinuity)

Longitudinal Study

Eosinopenia

10.1101/2021.05.26.442666

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Citations (44)

Trimodal single-cell profiling reveals a novel pediatric CD8αα+ T cell subset and broad age-related molecular reprogramming across the T cell compartment

Nature Immunology (2023)

Zachary Thomson Ziyuan He Elliott Swanson Katherine Henderson Cole Phalen

Abstract Age-associated changes in the T cell compartment are well described. However, limitations of current single-modal or bimodal single-cell assays, including flow cytometry, RNA-seq (RNA sequencing) and CITE-seq (cellular indexing of transcriptomes and epitopes by sequencing), have restricted our ability to deconvolve more complex cellular and molecular changes. Here, we profile >300,000 single T cells from healthy children (aged 11–13 years) and older adults (aged 55–65 years) by using the trimodal assay TEA-seq (single-cell analysis of mRNA transcripts, surface protein epitopes and chromatin accessibility), which revealed that molecular programming of T cell subsets shifts toward a more activated basal state with age. Naive CD4 + T cells, considered relatively resistant to aging, exhibited pronounced transcriptional and epigenetic reprogramming. Moreover, we discovered a novel CD8αα + T cell subset lost with age that is epigenetically poised for rapid effector responses and has distinct inhibitory, costimulatory and tissue-homing properties. Together, these data reveal new insights into age-associated changes in the T cell compartment that may contribute to differential immune responses.

Mass cytometry

Reprogramming

Single-Cell Analysis

Compartment (ship)

10.1038/s41590-023-01641-8

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Citations (17)

Cross‐platform immunophenotyping of human peripheral blood mononuclear cells with four high‐dimensional flow cytometry panels

Cytometry Part A (2022)

Alexander T. Heubeck Adam K. Savage Katherine Henderson Charles R. Roll Veronica Hernandez

Immunophenotyping using high dimensional flow cytometry is a central component of human immune system multi-omic studies. We present four high parameter flow cytometry panels for deep immunophenotyping of human peripheral blood mononuclear cells (PBMC). This set of four 25+ color panels include 64 cell surface markers to resolve broad immune compartment populations, as well as activation and memory of specific T, B, natural killer (NK), and myeloid lineages. Common lineage bridging markers are integrated into each panel to allow for inter-panel quality control through major lineage frequency verification. These panels were developed using a five laser BD Symphony A5 conventional cytometer and successfully transferred to a five laser Cytek Aurora spectral cytometer capable of acquiring the panels. Nine representative PBMC samples were stained with the four phenotyping panels and acquired on both instruments to evaluate population frequency and visual staining patterns for gating between the systems. Both instruments produced comparable high quality flow cytometry data and supported our decision to acquire samples on the spectral cytometer moving forward. This modular set of panels and instrument performance metrics provide guidelines for designing flow cytometry experiments suitable for longitudinal or cross-sectional immune profiling.

Immunophenotyping

Cytometry

Cluster of differentiation

Mass cytometry

10.1002/cyto.a.24715

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Citations (8)

Systemic inflammation and lymphocyte activation precede rheumatoid arthritis

bioRxiv (Cold Spring Harbor Laboratory) (2024)

Ziyuan He Marla C. Glass Pravina Venkatesan Marie L. Feser Leander Lazaro

Abstract Some autoimmune diseases, including rheumatoid arthritis (RA), are preceded by a critical subclinical phase of disease activity. Proactive clinical management is hampered by a lack of biological understanding of this subclinical ‘at-risk’ state and the changes underlying disease development. In a cross-sectional and longitudinal multi-omics study of peripheral immunity in the autoantibody-positive at-risk for RA period, we identified systemic inflammation, proinflammatory-skewed B cells, expanded Tfh17-like cells, epigenetic bias in naive T cells, TNF+IL1B+ monocytes resembling a synovial macrophage population, and CD4 T cell transcriptional features resembling those suppressed by abatacept (CTLA4-Ig) in RA patients. Our findings characterize pathogenesis prior to clinical diagnosis and suggest the at-risk state exhibits substantial immune alterations that could potentially be targeted for early intervention to delay or prevent autoimmunity. We provide a suite of tools at https://apps.allenimmunology.org/aifi/insights/ra-progression/ to facilitate exploration and enhance accessibility of this extensive dataset. One Sentence Summary ACPA+ at-risk individuals show RA-like inflammation and multi-compartment immune dysregulation during transition to clinically active RA

10.1101/2024.10.25.620344

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Distinct Heterogeneity in the Naive T cell Compartments of Children and Adults

bioRxiv (Cold Spring Harbor Laboratory) (2022)

Claire E. Gustafson Zachary Thomson Ziyuan He Elliott Swanson Katherine Henderson

Abstract: The naive T cell compartment undergoes multiple changes across age that associate with altered susceptibility to infection and autoimmunity. In addition to the acquisition of naive-like memory T cell subsets, mouse studies describe substantial molecular reprogramming of the naive compartment in adults compared with adolescents. However, these alterations are not well delineated in human aging. Using a new trimodal single cell technology (TEA-seq), we discovered that the composition and transcriptional and epigenetic programming of the naive T cell compartment in children (11-13 yrs) is distinct from that of older adults (55-65 yrs). Naive CD4 T cells, previously considered relatively resistant to aging, exhibited far more pronounced molecular reprogramming than naive CD8 T cells, in which alterations are preferentially driven by shifts in naive-like memory subsets. These data reveal the complex nature of the naive T cell compartment that may contribute to differential immune responses across the spectrum of human age. One Sentence Summary: The naive CD8 and CD4 T cell compartments in humans are heterogeneous and impacted differently with age, in which naive CD8 T cell subsets dramatically shift in composition and true naive CD4 T cells display significant molecular re-programming.

Compartment (ship)

Naive T cell

Reprogramming

10.1101/2022.10.04.510869

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Citations (2)

Sterile production of interferons in the thymus affects T cell repertoire selection

Science Immunology (2024)

K. Maude Ashby Matouš Vobořil Oscar Camilo Salgado S. Thera Lee Ryan J. Martinez

Type I and III interferons (IFNs) are robustly induced during infections and protect cells against viral infection. Both type I and III IFNs are also produced at low levels in the thymus at steady state; however, their role in T cell development and immune tolerance is unclear. Here, we found that both type I and III IFNs were constitutively produced by a very small number of AIRE + murine thymic epithelial cells, independent of microbial stimulation. Antigen-presenting cells were highly responsive to thymic IFNs, and IFNs were required for the activation and maturation of thymic type 1 conventional dendritic cells, macrophages, and B cells. Loss of IFN sensing led to reduced regulatory T cell selection, reduced T cell receptor (TCR) repertoire diversity, and enhanced autoreactive T cell responses to self-antigens expressed during peripheral IFN signaling. Thus, constitutive exposure to IFNs in the thymus is required for generating a tolerant and diverse TCR repertoire.

Central tolerance

Negative selection

10.1126/sciimmunol.adp1139

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Citations (4)