Quantitative Methodologies to Dissect Immune Cell Mechanobiology

Mechanobiology seeks to understand how cells integrate their biomechanics into their function and behavior. Unravelling the mechanisms underlying these mechanobiological processes is particularly important for immune cells in the context of the dynamic and complex tissue microenvironment. However, it remains largely unknown how cellular mechanical force generation and mechanical properties are regulated and integrated by immune cells, primarily due to a profound lack of technologies with sufficient sensitivity to quantify immune cell mechanics. In this review, we discuss the biological significance of mechanics for immune cells across length and time scales, and highlight several experimental methodologies for quantifying the mechanics of immune cells. Finally, we discuss the importance of quantifying the appropriate mechanical readout to accelerate insights into the mechanobiology of the immune response.

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Profiles of Peripheral Immune Cells of Uncomplicated COVID-19 Cases with Distinct Viral RNA Shedding Periods

Viruses ◽

10.3390/v13030514 ◽

2021 ◽

Vol 13 (3) ◽

pp. 514

Author(s):

Denise Utami Putri ◽

Cheng-Hui Wang ◽

Po-Chun Tseng ◽

Wen-Sen Lee ◽

Fu-Lun Chen ◽

...

Keyword(s):

Immune Response ◽

Immune Cells ◽

Mononuclear Cells ◽

Immune Cell ◽

Severe Disease ◽

Viral Rna ◽

Disease Course ◽

Peripheral Blood Mononuclear ◽

Peripheral Immune Cells ◽

Cell Profile

The heterogeneity of immune response to COVID-19 has been reported to correlate with disease severity and prognosis. While so, how the immune response progress along the period of viral RNA-shedding (VRS), which determines the infectiousness of disease, is yet to be elucidated. We aim to exhaustively evaluate the peripheral immune cells to expose the interplay of the immune system in uncomplicated COVID-19 cases with different VRS periods and dynamic changes of the immune cell profile in the prolonged cases. We prospectively recruited four uncomplicated COVID-19 patients and four healthy controls (HCs) and evaluated the immune cell profile throughout the disease course. Peripheral blood mononuclear cells (PBMCs) were collected and submitted to a multi-panel flowcytometric assay. CD19+-B cells were upregulated, while CD4, CD8, and NK cells were downregulated in prolonged VRS patients. Additionally, the pro-inflammatory-Th1 population showed downregulation, followed by improvement along the disease course, while the immunoregulatory cells showed upregulation with subsequent decline. COVID-19 patients with longer VRS expressed an immune profile comparable to those with severe disease, although they remained clinically stable. Further studies of immune signature in a larger cohort are warranted.

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Identification of immune-based prostate cancer subtypes using mRNA expression

10.21203/rs.2.23038/v1 ◽

2020 ◽

Author(s):

Jukun Song ◽

Song He ◽

Wei Wang ◽

Jiaming Su ◽

Dongbo Yuan ◽

...

Keyword(s):

Prostate Cancer ◽

Immune Response ◽

Immune Cells ◽

Immune Cell ◽

Molecular Classification ◽

Cell Types ◽

Functional Enrichment ◽

Cell Infiltration ◽

Cell Subpopulation ◽

Immune Cell Infiltration

Abstract Background Immune infiltration of Prostate cancer (PCa) was highly related to clinical outcomes. However, previous works failed to elucidate the diversity of different immune cell types that make up the function of the immune response system. The aim of the study was to uncover the composition of TIICs in PCa utilizing the CIBERSORT algorithm and further reveal the molecular characteristics of PCa subtypes. Method In the present work, we employed the CIBERSORT method to evaluate the relative proportions of immune cell profiling in PCa and adjacent samples, normal samples. We analyzed the correlation between immune cell infiltration and clinical information. The tumor-infiltrating immune cells of the TCGA PCa cohort were analyzed for the first time. The fractions of 22 immune cell types were imputed to determine the correlation between each immune cell subpopulation and clinical feature. Three types of molecular classification were identified via R-package of “CancerSubtypes”. The functional enrichment was analyzed in each subtype. The submap and TIDE algorithm were used to predict the clinical response to immune checkpoint blockade, and GDSC was employed to screen chemotherapeutic targets for the potential treatment of PCa. Results In current work, we utilized the CIBERSORT algorithm to assess the relative proportions of immune cell profiling in PCa and adjacent samples, normal samples. We investigated the correlation between immune cell infiltration and clinical data. The tumor-infiltrating immune cells in the TCGA PCa cohort were analyzed. The 22 immune cells were also calculated to determine the correlation between each immune cell subpopulation and survival and response to chemotherapy. Three types of molecular classification were identified. Each subtype has specific molecular and clinical characteristics. Meanwhile, Cluster I is defined as advanced PCa, and is more likely to respond to immunotherapy. Conclusions Our results demonstrated that differences in immune response may be important drivers of PCa progression and response to treatment. The deconvolution algorithm of gene expression microarray data by CIBERSOFT provides useful information about the immune cell composition of PCa patients. In addition, we have found a subtype of immunopositive PCa subtype and will help to explore the reasons for the poor effect of PCa on immunotherapy, and it is expected that immunotherapy will be used to guide the individualized management and treatment of PCa patients.

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The Hippo Pathway: Immunity and Cancer

Cancers ◽

10.3390/cancers10040094 ◽

2018 ◽

Vol 10 (4) ◽

pp. 94 ◽

Cited By ~ 38

Author(s):

Zaid Taha ◽

Helena Janse van Rensburg ◽

Xiaolong Yang

Keyword(s):

Immune Response ◽

Immune Cells ◽

Mammalian Cells ◽

Immune Cell ◽

Hippo Pathway ◽

Tissue Homeostasis ◽

Hippo Signaling ◽

Core Components ◽

The Hippo Pathway ◽

Future Work

Since its discovery, the Hippo pathway has emerged as a central signaling network in mammalian cells. Canonical signaling through the Hippo pathway core components (MST1/2, LATS1/2, YAP and TAZ) is important for development and tissue homeostasis while aberrant signaling through the Hippo pathway has been implicated in multiple pathologies, including cancer. Recent studies have uncovered new roles for the Hippo pathway in immunology. In this review, we summarize the mechanisms by which Hippo signaling in pathogen-infected or neoplastic cells affects the activities of immune cells that respond to these threats. We further discuss how Hippo signaling functions as part of an immune response. Finally, we review how immune cell-intrinsic Hippo signaling modulates the development/function of leukocytes and propose directions for future work.

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Multi-modal single cell analysis reveals brain immune landscape plasticity during aging and gut microbiota dysbiosis

10.1101/2020.07.15.205377 ◽

2020 ◽

Author(s):

Samantha M. Golomb ◽

Ian H. Guldner ◽

Anqi Zhao ◽

Qingfei Wang ◽

Bhavana Palakurthi ◽

...

Keyword(s):

Single Cell ◽

Immune Cells ◽

Immune Cell ◽

Cell Types ◽

Cell Plasticity ◽

Tissue Microenvironment ◽

Gut Dysbiosis ◽

Resolution Single ◽

The Brain ◽

Gut Microbiota Dysbiosis

ABSTRACTThe brain contains a diverse array of immune cell types. The phenotypic and functional plasticity of brain immune cells collectively contribute to brain tissue homeostasis and disease progression. Immune cell plasticity is profoundly influenced by local tissue microenvironment cues and systemic factors. Yet, the transcriptional mechanism by which systemic stimuli, such as aging and gut microbiota dysbiosis, reshape brain immune cell plasticity and homeostasis has not been fully delineated. Using Cellular Indexing of Transcriptomes and Epitopes by sequencing (CITE-seq), we analyzed compositional and transcriptional changes of the brain immune landscape in response to aging and gut dysbiosis. We first examined the discordance between canonical surface marker-defined immune cell types (Cell-ID) and their transcriptome signatures, which suggested transcriptional plasticity among immune cells despite sharing the same cell surface markers. Specifically, inflammatory and patrolling Ly6C+ monocytes were shifted predominantly to a pro-inflammatory transcriptional program in the aged brain, while brain ILCs shifted toward an ILC2 transcriptional profile. Finally, aging led to an increase of ILC-like cells expressing a T memory stemness (Tscm) signature in the brain. Antibiotics (ABX)-induced gut dysbiosis reduced the frequency of ILCs exhibiting Tscm-like properties in the aged mice, but not in the young mice. Enabled by high-resolution single-cell molecular phenotyping, our study revealed that systemic changes due to aging and gut dysbiosis prime the brain environment for an increased propensity for neuroinflammation, which provided insights into gut dysbiosis in age-related neurological diseases.Manuscript SummaryGolomb et al. performed Cellular Indexing of Transcriptomes and Epitopes by sequencing (CITE-seq) on immune cells from the brains of young and aged mice with and without antibiotics-induced gut dysbiosis. High resolution, single cell immunophenotyping enabled the dissection of extensive transcriptional plasticity of canonically identified monocytes and innate lymphoid cells (ILCs) in the aged brain. Through differential gene expression and trajectory inference analyses, the authors revealed tissue microenvironment-dependent cellular responses influenced by aging and gut dysbiosis that may potentiate neuroinflammatory diseases.Graphical Abstract

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TrackSOM: mapping immune response dynamics through sequential clustering of time- and disease-course single-cell cytometry data

10.1101/2021.06.08.447468 ◽

2021 ◽

Author(s):

Givanna Haryono Putri ◽

Jonathan Chung ◽

Davis N Edwards ◽

Felix Marsh-Wakefield ◽

Suat Dervish ◽

...

Keyword(s):

Immune Response ◽

Immune System ◽

West Nile Virus ◽

Immune Cells ◽

Immune Cell ◽

West Nile Virus Infection ◽

Cell Populations ◽

Disease Course ◽

Response Dynamics ◽

Over Time

Mapping the dynamics of immune cell populations over time or disease-course is key to understanding immunopathogenesis and devising putative interventions. We present TrackSOM, an algorithm which delineates cellular populations and tracks their development over a time- or disease-course of cytometry datasets. We demonstrate TrackSOM-enabled elucidation of the immune response to West Nile Virus infection in mice, uncovering heterogeneous sub-populations of immune cells and relating their functional evolution to disease severity. TrackSOM is easy to use, encompasses few parameters, is quick to execute, and enables an integrative and dynamic overview of the immune system kinetics that underlie disease progression and/or resolution.

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The immune response and aging in chronic inflammatory demyelinating polyradiculoneuropathy

Journal of Neuroinflammation ◽

10.1186/s12974-021-02113-2 ◽

2021 ◽

Vol 18 (1) ◽

Cited By ~ 1

Author(s):

Kathleen M. Hagen ◽

Shalina S. Ousman

Keyword(s):

Immune Response ◽

Immune Cells ◽

Older Patients ◽

Potential Role ◽

Immune Cell ◽

Chronic Inflammatory Demyelinating Polyradiculoneuropathy ◽

Cell Populations ◽

Relapsing Remitting ◽

Progressive Course

AbstractChronic inflammatory demyelinating polyradiculoneuropathy (CIDP) consists of various autoimmune subtypes in which the peripheral nervous system (PNS) is attacked. CIDP can follow a relapsing-remitting or progressive course where the resultant demyelination caused by immune cells (e.g., T cells, macrophages) and antibodies can lead to disability in patients. Importantly, the age of CIDP patients has a role in their symptomology and specific variants have been associated with differing ages of onset. Furthermore, older patients have a decreased frequency of functional recovery after CIDP insult. This may be related to perturbations in immune cell populations that could exacerbate the disease with increasing age. In the present review, the immune profile of typical CIDP will be discussed followed by inferences into the potential role of relevant aging immune cell populations. Atypical variants will also be briefly reviewed followed by an examination of the available studies on the immunology underlying them.

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Hypoxia/HIF Modulates Immune Responses

Biomedicines ◽

10.3390/biomedicines9030260 ◽

2021 ◽

Vol 9 (3) ◽

pp. 260

Author(s):

Yuling Chen ◽

Timo Gaber

Keyword(s):

Immune Response ◽

Cancer Progression ◽

Immune Cells ◽

Cell Function ◽

Immune Cell ◽

Adaptive Immune Response ◽

Oxygen Availability ◽

The Body ◽

Low Oxygen ◽

Adaptive Immune

Oxygen availability varies throughout the human body in health and disease. Under physiological conditions, oxygen availability drops from the lungs over the blood stream towards the different tissues into the cells and the mitochondrial cavities leading to physiological low oxygen conditions or physiological hypoxia in all organs including primary lymphoid organs. Moreover, immune cells travel throughout the body searching for damaged cells and foreign antigens facing a variety of oxygen levels. Consequently, physiological hypoxia impacts immune cell function finally controlling innate and adaptive immune response mainly by transcriptional regulation via hypoxia-inducible factors (HIFs). Under pathophysiological conditions such as found in inflammation, injury, infection, ischemia and cancer, severe hypoxia can alter immune cells leading to dysfunctional immune response finally leading to tissue damage, cancer progression and autoimmunity. Here we summarize the effects of physiological and pathophysiological hypoxia on innate and adaptive immune activity, we provide an overview on the control of immune response by cellular hypoxia-induced pathways with focus on the role of HIFs and discuss the opportunity to target hypoxia-sensitive pathways for the treatment of cancer and autoimmunity.

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Allometric tissue-scale forces activate mechanoresponsive immune cells to drive pathological foreign body response to biomedical implants

10.1101/2022.01.14.476395 ◽

2022 ◽

Author(s):

Jagannath Padmanabhan ◽

Kellen Chen ◽

Dharshan Sivaraj ◽

Britta A Kuehlmann ◽

Clark A Bonham ◽

...

Keyword(s):

Mechanical Properties ◽

Foreign Body ◽

Immune Cells ◽

Immune Cell ◽

Implantable Devices ◽

Foreign Body Response ◽

Biomedical Implants ◽

Independent Variable ◽

First Time ◽

Body Response

For decades, it has been assumed that the foreign body response (FBR) to biomedical implants is primarily a reaction to the chemical and mechanical properties of the implant. Here, we show for the first time that a third independent variable, allometric tissue-scale forces (which increase exponentially with body size), can drive the biology of FBR in humans. We first demonstrate that pathological FBR in humans is mediated by immune cell-specific Rac2 mechanotransduction signaling, independent of implant chemistry or mechanical properties. We then show that mice, which are typically poor models of human FBR, can be made to induce a strikingly human-like pathological FBR by altering these extrinsic tissue forces. Altering these extrinsic tissue forces alone activates Rac2 signaling in a unique subpopulation of immune cells and results in a human-like pathological FBR at the molecular, cellular, and local tissue levels. Finally, we demonstrate that blocking Rac2 signaling negates the effect of increased tissue forces, dramatically reducing FBR. These findings highlight a previously unsuspected mechanism for pathological FBR and may have profound implications for the design and safety of all implantable devices in humans.

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Maternal vitamin D deficiency increases the risk of obesity in male mice offspring by affecting the immune response

10.1101/2020.03.23.004721 ◽

2020 ◽

Author(s):

Pei Li ◽

Ping Li ◽

Yuanlin Liu ◽

Weijiang Liu ◽

Lanlan Zha ◽

...

Keyword(s):

Immune Response ◽

Immune Cells ◽

Immune Cell ◽

Male Offspring ◽

Inflammatory Factors ◽

Cell Populations ◽

Male Mice ◽

Gene Expressions ◽

M1 Macrophage ◽

Obese Male

AbstractRecently, many epidemiological and animal studies have indicated that obesity have their origin in the early stages of life including the inappropriate balance of some nutrients, the objective of this study is to determine the risk of obesity in male mice offspring as a consequence of maternal VD deficiency-mediated disordering of the immune response. Four-week-old C57BL/6J female mice were fed VD-deficient or normal reproductive diets during pregnancy and lactation. Their male offspring were weighted and euthanized after being fed control and high-fat diets (HFD) for 16 weeks starting at the weaning. The serum was collected for biochemical analyses. Epididymal (eWAT) and inguinal (iWAT) white adipose tissues were excised for histological examination, immunohistochemistry, gene expressions of inflammatory factors, and for determining the proportions of immune cells by flow cytometry. Insufficient maternal VD intake exacerbated the development of obesity both in non-obese and obese male offspring as evidenced by larger adipose cells and abnormal glucose and lipid metabolisms. Also, the expression of proinflammatory cytokine genes was increased and that of anti-inflammatory cytokines was decreased in maternal VD-deficient groups in the eWAT and/or iWAT. This was accompanied by higher levels of TNF-α or/and INF-β, and lower levels of IL-4 and IL-10. Insufficient maternal VD intake was also observed to induce a shift in the profiles of immune cells in the eWAT and/or iWAT, resulting in increased percentages of M1 macrophage, ATDCs, and CD4+ and CD8+ T cells, but caused a significant decrease in the percentage of M2 macrophages, both in non-obese and obese male offspring. All these changes in the immune cell profile were more obvious in the eWAT than in the iWAT. These results indicated that insufficient maternal VD intake promoted the development of obesity in male offspring by modulating the immune cell populations and causing a polarization in the adipose depots.ImportanceEvidence in this study has indicated that insufficient maternal VD intake promotes the development of obesity in the male offspring by modulating the recruitment of immune cell populations and their polarization as well as the expression and secretion of proinflammatory adipokines in the adipose depots in a weight-independent manner, which is more obvious in eWAT than that in the iWAT.

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Single-Cell RNA Sequencing of Peripheral Blood Reveals Immune Cell Signatures in Alzheimer’s Disease

Frontiers in Immunology ◽

10.3389/fimmu.2021.645666 ◽

2021 ◽

Vol 12 ◽

Author(s):

Hui Xu ◽

Jianping Jia

Keyword(s):

Immune Response ◽

T Cells ◽

Single Cell ◽

Immune Cells ◽

Peripheral Blood ◽

Immune Cell ◽

Adaptive Immune Response ◽

Immune Repertoire ◽

Adaptive Immune ◽

Peripheral Immune Cells

The peripheral immune system is thought to affect the pathology of the central nervous system in Alzheimer’s disease (AD). However, current knowledge is inadequate for understanding the characteristics of peripheral immune cells in AD. This study aimed to explore the molecular basis of peripheral immune cells and the features of adaptive immune repertoire at a single cell level. We profiled 36,849 peripheral blood mononuclear cells from AD patients with amyloid-positive status and normal controls with amyloid-negative status by 5’ single-cell transcriptome and immune repertoire sequencing using the cell ranger standard analysis procedure. We revealed five immune cell subsets: CD4+ T cells, CD8+ T cells, B cells, natural killer cells, and monocytes–macrophages cells, and disentangled the characteristic alterations of cell subset proportion and gene expression patterns in AD. Thirty-one cell type-specific key genes, comprising abundant human leukocyte antigen genes, and multiple immune-related pathways were identified by protein–protein interaction network and pathway enrichment analysis. We also found high-frequency amplification clonotypes in T and B cells and decreased diversity in T cells in AD. As clone amplification suggested the activation of an adaptive immune response against specific antigens, we speculated that the peripheral adaptive immune response, especially mediated by T cells, may have a role in the pathogenesis of AD. This finding may also contribute to further research regarding disease mechanism and the development of immune-related biomarkers or therapy.

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