A Novel Inflammatory Dendritic Cell That Is Abundant and Contiguous to T Cells in the Kidneys of Patients With Lupus Nephritis

The mechanisms that promote local inflammatory injury during lupus nephritis (LN) flare are largely unknown. Understanding the key immune cells that drive intrarenal inflammation will advance our knowledge of disease pathogenesis and inform the development of new therapeutics for LN management. In this study, we analyzed kidney biopsies from patients with proliferative LN and identified a novel inflammatory dendritic cell (infDC) population that is highly expressed in the LN kidney, but minimally present in healthy human kidneys. During an agnostic evaluation of immune transcript expression in the kidneys of patients with proliferative LN, the most abundantly overexpressed transcript from isolated glomeruli was FCER1G, which encodes the Fc receptor gamma chain (FcRγ). To identify the cell types expressing FcRγ that infiltrate the kidney in LN, studies were done on kidney biopsies from patients with active LN using confocal immunofluorescence (IF) microscopy. This showed that FcRγ is abundantly present in the periglomerular (PG) region of the kidney and to a lesser extent in the tubulointerstitium (TI). Further investigation of the surface markers of these cells showed that they were FcRγ+, MHC II+, CD11c+, CD163+, CD5−, DC-SIGN+, CD64+, CD14+, CD16+, SIRPα+, CD206−, CD68−, CD123−, CD3−, and CD11b−, suggesting the cells were infDCs. Quantification of the infDCs showed an average 10-fold higher level of infDCs in the LN kidney compared to the healthy kidneys. Importantly, IF identified CD3+ T cells to be adjacent to these infDCs in the PG space of the LN kidney, whereas both cell types are minimally present in the healthy kidney. Thus, we have identified a previously undescribed DC in lupus kidneys that may interact with intrarenal T cells and play a role in the pathogenesis of kidney injury during LN flare.

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Crosstalk Between Tumor-Associated Microglia/Macrophages and CD8-Positive T Cells Plays a Key Role in Glioblastoma

Frontiers in Immunology ◽

10.3389/fimmu.2021.650105 ◽

2021 ◽

Vol 12 ◽

Author(s):

Sheng Tu ◽

Xu Lin ◽

Jili Qiu ◽

Jiaqi Zhou ◽

Hui Wang ◽

...

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Immune Cells ◽

Malignant Disease ◽

Immune Therapy ◽

Cell Types ◽

Different Types ◽

The Central Nervous System ◽

And Function ◽

The Relationship

Glioblastoma is considered to be the most malignant disease of the central nervous system, and it is often associated with poor survival. The immune microenvironment plays a key role in the development and treatment of glioblastoma. Among the different types of immune cells, tumor-associated microglia/macrophages (TAM/Ms) and CD8-positive (CD8+) T cells are the predominant immune cells, as well as the most active ones. Current studies have suggested that interaction between TAM/Ms and CD8+ T cells have numerous potential targets that will allow them to overcome malignancy in glioblastoma. In this review, we summarize the mechanism and function of TAM/Ms and CD8+ T cells involved in glioblastoma, as well as update on the relationship and crosstalk between these two cell types, to determine whether this association alters the immune status during glioblastoma development and affects optimal treatment. We focus on the molecular factors that are crucial to this interaction, and the role that this crosstalk plays in the biological processes underlying glioblastoma treatment, particularly with regard to immune therapy. We also discuss novel therapeutic targets that can aid in resolving reticular connections between TAM/Ms and CD8+ T cells, including depletion and reprogramming TAM/Ms and novel TAM/Ms-CD8+ T cell cofactors with potential translational usage. In addition, we highlight the challenges and discuss future perspectives of this crosstalk between TAM/Ms and CD8+ T cells.

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Knowledge-based classification of fine-grained immune cell types in single-cell RNA-Seq data with ImmClassifier

10.1101/2020.03.23.002758 ◽

2020 ◽

Author(s):

Xuan Liu ◽

Sara J.C. Gosline ◽

Lance T. Pflieger ◽

Pierre Wallet ◽

Archana Iyer ◽

...

Keyword(s):

T Cells ◽

Single Cell ◽

Immune Cells ◽

Immune Cell ◽

Cell Types ◽

Effector Memory ◽

Immune Cell Population ◽

Fine Grained ◽

Knowledge Based ◽

Comparable Performance

AbstractSingle-cell RNA sequencing is an emerging strategy for characterizing the immune cell population in diverse environments including blood, tumor or healthy tissues. While this has traditionally been done with flow or mass cytometry targeting protein expression, scRNA-Seq has several established and potential advantages in that it can profile immune cells and non-immune cells (e.g. cancer cells) in the same sample, identify cell types that lack precise markers for flow cytometry, or identify a potentially larger number of immune cell types and activation states than is achievable in a single flow assay. However, scRNA-Seq is currently limited due to the need to identify the types of each immune cell from its transcriptional profile, which is not only time-consuming but also requires a significant knowledge of immunology. While recently developed algorithms accurately annotate coarse cell types (e.g. T cells vs macrophages), making fine distinctions has turned out to be a difficult challenge. To address this, we developed a machine learning classifier called ImmClassifier that leverages a hierarchical ontology of cell type. We demonstrate that ImmClassifier outperforms other tools (+20% recall, +14% precision) in distinguishing fine-grained cell types (e.g. CD8+ effector memory T cells) with comparable performance on coarse ones. Thus, ImmClassifier can be used to explore more deeply the heterogeneity of the immune system in scRNA-Seq experiments.

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Total CD3 T Cells Are Necessary and Sufficient to Induce Colitis in Immunodeficient Mice With Dendritic Cell–Specific Deletion of TGFbR2: A Novel IBD Model to Study CD4 and CD8 T-Cell Interaction

Inflammatory Bowel Diseases ◽

10.1093/ibd/izz191 ◽

2019 ◽

Vol 26 (2) ◽

pp. 229-241

Author(s):

Deepa Rana Jamwal ◽

Raji V Marati ◽

Christy A Harrison ◽

Monica T Midura-Kiela ◽

Vanessa R Figliuolo Paz ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Dendritic Cell ◽

Cd8 T Cells ◽

Immune Cells ◽

Immune Cell ◽

Immunodeficient Mice ◽

Cell Lineages ◽

Adaptive Immune ◽

Adaptive Immune Cells

Abstract Background Inflammatory bowel disease (IBD) is a multifactorial disorder, with the innate and adaptive immune cells contributing to disease initiation and progression. However, the intricate cross-talk between immune cell lineages remains incompletely understood. The role of CD8+ T cells in IBD pathogenesis has been understudied, largely due to the lack of appropriate models. Methods We previously reported spontaneous colitis in mice with impaired TGFβ signaling due to dendritic cell–specific knockout of TGFbR2 (TGFβR2ΔDC). Here, we demonstrate that crossing TGFβR2ΔDC mice with a Rag1-/- background eliminates all symptoms of colitis and that adoptive transfer of unfractionated CD3+ splenocytes is sufficient to induce progressive colitis in Rag1-/-TGFβR2ΔDC mice. Results Both CD4+ and CD8+ T cells are required for the induction of colitis accompanied by activation of both T-cell lineages and DCs, increased expression of mucosal IFNγ, TNFα, IL6, IL1β, and IL12, and decreased frequencies of CD4+FoxP3+ regulatory T cells. Development of colitis required CD40L expression in CD4+ T cells, and the disease was partially ameliorated by IFNγ neutralization. Conclusions This novel model provides an important tool for studying IBD pathogenesis, in particular the complex interactions among innate and adaptive immune cells in a controlled fashion, and represents a valuable tool for preclinical evaluation of novel therapeutics.

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Authentic Patient-Derived Hepatitis C Virus Infects and Productively Replicates in Primary CD4+and CD8+T LymphocytesIn Vitro

Journal of Virology ◽

10.1128/jvi.01790-17 ◽

2017 ◽

Vol 92 (3) ◽

Cited By ~ 4

Author(s):

Georgia Skardasi ◽

Annie Y. Chen ◽

Tomasz I. Michalak

Keyword(s):

T Cells ◽

Hepatitis C Virus ◽

Hepatitis C ◽

T Lymphocytes ◽

Immune Cells ◽

Immune Cell ◽

Cell Types ◽

Hcv Rna ◽

Biophysical Properties

ABSTRACTAccumulated evidence indicates that immune cells can support the replication of hepatitis C virus (HCV) in infected patients and in culture. However, there is a scarcity of data on the degree to which individual immune cell types support HCV propagation and on characteristics of virus assembly. We investigated the ability of authentic, patient-derived HCV to infectin vitrotwo closely related but functionally distinct immune cell types, CD4+and CD8+T lymphocytes, and assessed the properties of the virus produced by these cells. The HCV replication system in intermittently mitogen-stimulated T cells was adapted to infect primary human CD4+or CD8+T lymphocytes. HCV replicated in both cell types although at significantly higher levels in CD4+than in CD8+T cells. Thus, the HCV RNA replicative (negative) strand was detected in CD4+and CD8+cells at estimated mean levels ± standard errors of the means of 6.7 × 102± 3.8 × 102and 1.2 × 102± 0.8 × 102copies/μg RNA, respectively (P< 0.0001). Intracellular HCV NS5a and/or core proteins were identified in 0.9% of CD4+and in 1.2% of CD8+T cells. Double staining for NS5a and T cell type-specific markers confirmed that transcriptionally competent virus replicated in both cell types. Furthermore, an HCV-specific protease inhibitor, telaprevir, inhibited infection in both CD4+and CD8+cells. The emergence of unique HCV variants and the release of HCV RNA-reactive particles with biophysical properties different from those of virions in plasma inocula suggested that distinct viral particles were assembled, and therefore, they may contribute to the pool of circulating virus in infected patients.IMPORTANCEAlthough the liver is the main site of HCV replication, infection of the immune system is an intrinsic characteristic of this virus independent of whether infection is symptomatic or clinically silent. Many fundamental aspects of HCV lymphotropism remain uncertain, including the degree to which different immune cells support infection and contribute to virus diversity. We show that authentic, patient-derived HCV productively replicatesin vitroin two closely related but functionally distinct types of T lymphocytes, CD4+and CD8+cells. The display of viral proteins and unique variants, the production of virions with biophysical properties distinct from those in plasma serving as inocula, and inhibition of replication by an antiviral agent led us to ascertain that both T cell subtypes supported virus propagation. Infection of CD4+and CD8+T cells, which are central to adaptive antiviral immune responses, can directly affect HCV clearance, favor virus persistence, and decisively influence the development and progression of hepatitis C.

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Lamin A/C and the Immune System: One Intermediate Filament, Many Faces

International Journal of Molecular Sciences ◽

10.3390/ijms21176109 ◽

2020 ◽

Vol 21 (17) ◽

pp. 6109

Author(s):

Angela Saez ◽

Beatriz Herrero-Fernandez ◽

Raquel Gomez-Bris ◽

Beatriz Somovilla-Crespo ◽

Cristina Rius ◽

...

Keyword(s):

T Cells ◽

Immune System ◽

Adaptive Immunity ◽

Immune Cells ◽

Cell Cycle Progression ◽

Cell Types ◽

Lamin A ◽

Nuclear Mechanics ◽

Adaptive Immune Cells ◽

C Proteins

Nuclear envelope lamin A/C proteins are a major component of the mammalian nuclear lamina, a dense fibrous protein meshwork located in the nuclear interior. Lamin A/C proteins regulate nuclear mechanics and structure and control cellular signaling, gene transcription, epigenetic regulation, cell cycle progression, cell differentiation, and cell migration. The immune system is composed of the innate and adaptive branches. Innate immunity is mediated by myeloid cells such as neutrophils, macrophages, and dendritic cells. These cells produce a rapid and nonspecific response through phagocytosis, cytokine production, and complement activation, as well as activating adaptive immunity. Specific adaptive immunity is activated by antigen presentation by antigen presenting cells (APCs) and the cytokine microenvironment, and is mainly mediated by the cellular functions of T cells and the production of antibodies by B cells. Unlike most cell types, immune cells regulate their lamin A/C protein expression relatively rapidly to exert their functions, with expression increasing in macrophages, reducing in neutrophils, and increasing transiently in T cells. In this review, we discuss and summarize studies that have addressed the role played by lamin A/C in the functions of innate and adaptive immune cells in the context of human inflammatory and autoimmune diseases, pathogen infections, and cancer.

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Classical MHC expression by DP thymocytes impairs the selection of non-classical MHC restricted innate-like T cells

Nature Communications ◽

10.1038/s41467-021-22589-z ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Hristo Georgiev ◽

Changwei Peng ◽

Matthew A. Huggins ◽

Stephen C. Jameson ◽

Kristin A. Hogquist

Keyword(s):

T Cells ◽

Epithelial Cells ◽

Cell Types ◽

Inkt Cells ◽

Mhc I ◽

Mait Cells ◽

Mhc Molecules ◽

Mhc Ii ◽

Different Cell Types ◽

Selection Of

AbstractConventional T cells are selected by peptide-MHC expressed by cortical epithelial cells in the thymus, and not by cortical thymocytes themselves that do not express MHC I or MHC II. Instead, cortical thymocytes express non-peptide presenting MHC molecules like CD1d and MR1, and promote the selection of PLZF+ iNKT and MAIT cells, respectively. Here, we report an inducible class-I transactivator mouse that enables the expression of peptide presenting MHC I molecules in different cell types. We show that MHC I expression in DP thymocytes leads to expansion of peptide specific PLZF+ innate-like (PIL) T cells. Akin to iNKT cells, PIL T cells differentiate into three functional effector subsets in the thymus, and are dependent on SAP signaling. We demonstrate that PIL and NKT cells compete for a narrow niche, suggesting that the absence of peptide-MHC on DP thymocytes facilitates selection of non-peptide specific lymphocytes.

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Reference Transcriptomes of Porcine Peripheral Immune Cells Created Through Bulk and Single-Cell RNA Sequencing

Frontiers in Genetics ◽

10.3389/fgene.2021.689406 ◽

2021 ◽

Vol 12 ◽

Author(s):

Juber Herrera-Uribe ◽

Jayne E. Wiarda ◽

Sathesh K. Sivasankaran ◽

Lance Daharsh ◽

Haibo Liu ◽

...

Keyword(s):

T Cells ◽

Single Cell ◽

Immune Cells ◽

Peripheral Blood ◽

Cell Types ◽

Cell Populations ◽

Rna Seq ◽

Cell Type ◽

Transcriptomic Data ◽

Single Cell Rna Sequencing

Pigs are a valuable human biomedical model and an important protein source supporting global food security. The transcriptomes of peripheral blood immune cells in pigs were defined at the bulk cell-type and single cell levels. First, eight cell types were isolated in bulk from peripheral blood mononuclear cells (PBMCs) by cell sorting, representing Myeloid, NK cells and specific populations of T and B-cells. Transcriptomes for each bulk population of cells were generated by RNA-seq with 10,974 expressed genes detected. Pairwise comparisons between cell types revealed specific expression, while enrichment analysis identified 1,885 to 3,591 significantly enriched genes across all 8 cell types. Gene Ontology analysis for the top 25% of significantly enriched genes (SEG) showed high enrichment of biological processes related to the nature of each cell type. Comparison of gene expression indicated highly significant correlations between pig cells and corresponding human PBMC bulk RNA-seq data available in Haemopedia. Second, higher resolution of distinct cell populations was obtained by single-cell RNA-sequencing (scRNA-seq) of PBMC. Seven PBMC samples were partitioned and sequenced that produced 28,810 single cell transcriptomes distributed across 36 clusters and classified into 13 general cell types including plasmacytoid dendritic cells (DC), conventional DCs, monocytes, B-cell, conventional CD4 and CD8 αβ T-cells, NK cells, and γδ T-cells. Signature gene sets from the human Haemopedia data were assessed for relative enrichment in genes expressed in pig cells and integration of pig scRNA-seq with a public human scRNA-seq dataset provided further validation for similarity between human and pig data. The sorted porcine bulk RNAseq dataset informed classification of scRNA-seq PBMC populations; specifically, an integration of the datasets showed that the pig bulk RNAseq data helped define the CD4CD8 double-positive T-cell populations in the scRNA-seq data. Overall, the data provides deep and well-validated transcriptomic data from sorted PBMC populations and the first single-cell transcriptomic data for porcine PBMCs. This resource will be invaluable for annotation of pig genes controlling immunogenetic traits as part of the porcine Functional Annotation of Animal Genomes (FAANG) project, as well as further study of, and development of new reagents for, porcine immunology.

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Single-Cell Profiling of Kidney Transplant Recipients With Immunosuppressive Treatment Reveals the Dynamic Immune Characteristics

Frontiers in Immunology ◽

10.3389/fimmu.2021.639942 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yongguang Liu ◽

Xiaoyou Liu ◽

Song Zhou ◽

Ruiquan Xu ◽

Jianmin Hu ◽

...

Keyword(s):

T Cells ◽

Kidney Transplantation ◽

Cd8 T Cells ◽

Immune Cells ◽

Peripheral Blood ◽

Cd4 T Cells ◽

Immune Cell ◽

Immunosuppressive Agents ◽

Cell Types ◽

Before And After

Kidney transplantation is currently the first choice of treatment for various types of end-stage renal failure, but there are major limitations in the application of immunosuppressive protocols after kidney transplantation. When the dose of immunosuppressant is too low, graft rejection occurs easily, while a dose that is too high can lead to graft loss. Therefore, it is very important to explore the immune status of patients receiving immunosuppressive agents after kidney transplantation. To compare the immune status of the recipient’s whole peripheral blood before and after receipt of immunosuppressive agents, we used single-cell cytometry by time-of-flight (CyTOF) to detect the peripheral blood immune cells in five kidney transplant recipients (KTRs) from the Department of Organ Transplantation of Zhujiang Hospital of Southern Medical University before and after receiving immunosuppressive agents. Based on CyTOF analysis, we detected 363,342 live single immune cells. We found that the immune cell types of the KTRs before and after receipt of immunosuppressive agents were mainly divided into CD4+ T cells, CD8+ T cells, B cells, NK cells/γδ T cells, monocytes/macrophages, granulocytes, and dendritic cells (DCs). After further reclustering of the above cell types, it was found that the immune cell subclusters in the peripheral blood of patients underwent major changes after receipt of immunosuppressants. After receiving immunosuppressive therapy, the peripheral blood of KTRs had significantly increased levels of CD57+NK cells and significantly decreased levels of central memory CD4+ T cells, follicular helper CD4+ T cells, effector CD8+ T cells, effector memory CD8+ T cells and naive CD8+ T cells. This study used CyTOF to classify immune cells in the peripheral blood of KTRs before and after immunosuppressive treatment, further compared differences in the proportions of the main immune cell types and immune cell subgroups before and after receipt of immunosuppressants, and provided relatively accurate information for assessment and treatment strategies for KTRs.

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RUN and FYVE domain–containing protein 4 enhances autophagy and lysosome tethering in response to Interleukin-4

The Journal of Cell Biology ◽

10.1083/jcb.201501059 ◽

2015 ◽

Vol 210 (7) ◽

pp. 1133-1152 ◽

Cited By ~ 36

Author(s):

Seigo Terawaki ◽

Voahirana Camosseto ◽

Francesca Prete ◽

Till Wenger ◽

Alexia Papadopoulos ◽

...

Keyword(s):

Immune Cells ◽

Pathogen Detection ◽

Cell Types ◽

Interleukin 4 ◽

Autophagosome Formation ◽

Autophagy Flux ◽

Mhc Ii ◽

Fyve Domain ◽

Distinct Cell

Autophagy is a key degradative pathway coordinated by external cues, including starvation, oxidative stress, or pathogen detection. Rare are the molecules known to contribute mechanistically to the regulation of autophagy and expressed specifically in particular environmental contexts or in distinct cell types. Here, we unravel the role of RUN and FYVE domain–containing protein 4 (RUFY4) as a positive molecular regulator of macroautophagy in primary dendritic cells (DCs). We show that exposure to interleukin-4 (IL-4) during DC differentiation enhances autophagy flux through mTORC1 regulation and RUFY4 induction, which in turn actively promote LC3 degradation, Syntaxin 17–positive autophagosome formation, and lysosome tethering. Enhanced autophagy boosts endogenous antigen presentation by MHC II and allows host control of Brucella abortus replication in IL-4–treated DCs and in RUFY4-expressing cells. RUFY4 is therefore the first molecule characterized to date that promotes autophagy and influences endosome dynamics in a subset of immune cells.

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Role of Methylation in Pro- and Anti-Cancer Immunity

Cancers ◽

10.3390/cancers13030545 ◽

2021 ◽

Vol 13 (3) ◽

pp. 545

Author(s):

Ali Mehdi ◽

Shafaat A. Rabbani

Keyword(s):

T Cells ◽

Transcriptional Regulation ◽

Immune Cells ◽

Cell Types ◽

Rna Methylation ◽

Dna And Rna ◽

Cancer Immunity ◽

Anti Cancer ◽

And Function

DNA and RNA methylation play a vital role in the transcriptional regulation of various cell types including the differentiation and function of immune cells involved in pro- and anti-cancer immunity. Interactions of tumor and immune cells in the tumor microenvironment (TME) are complex. TME shapes the fate of tumors by modulating the dynamic DNA (and RNA) methylation patterns of these immune cells to alter their differentiation into pro-cancer (e.g., regulatory T cells) or anti-cancer (e.g., CD8+ T cells) cell types. This review considers the role of DNA and RNA methylation in myeloid and lymphoid cells in the activation, differentiation, and function that control the innate and adaptive immune responses in cancer and non-cancer contexts. Understanding the complex transcriptional regulation modulating differentiation and function of immune cells can help identify and validate therapeutic targets aimed at targeting DNA and RNA methylation to reduce cancer-associated morbidity and mortality.

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