Faculty Opinions recommendation of IL-10 is up-regulated in multiple cell types during viremic HIV infection and reversibly inhibits virus-specific T cells.

2010 ◽  
Author(s):  
Susana Asin ◽  
Christiane Rollenhagen
Keyword(s):  
T Cells ◽  
Hiv Infection ◽  
Cell Types ◽  
Multiple Cell

scholarly journals IL-10 is up-regulated in multiple cell types during viremic HIV infection and reversibly inhibits virus-specific T cells

Blood ◽  
2009 ◽  
Vol 114 (2) ◽  
pp. 346-356 ◽  
Author(s):  
Mark A. Brockman ◽  
Douglas S. Kwon ◽  
Daniel P. Tighe ◽  
David F. Pavlik ◽  
Pamela C. Rosato ◽  
...  
Keyword(s):  
T Cells ◽  
Hiv Infection ◽  
Mononuclear Cells ◽  
Cell Function ◽  
Cell Types ◽  
Interleukin 10 ◽  
Mrna Levels ◽  
Peripheral Blood Mononuclear ◽  
Multiple Cell

AbstractMurine models indicate that interleukin-10 (IL-10) can suppress viral clearance, and interventional blockade of IL-10 activity has been proposed to enhance immunity in chronic viral infections. Increased IL-10 levels have been observed during HIV infection and IL-10 blockade has been shown to enhance T-cell function in some HIV-infected subjects. However, the categories of individuals in whom the IL-10 pathway is up-regulated are poorly defined, and the cellular sources of IL-10 in these subjects remain to be determined. Here we report that blockade of the IL-10 pathway augmented in vitro proliferative capacity of HIV-specific CD4 and CD8 T cells in individuals with ongoing viral replication. IL-10 blockade also increased cytokine secretion by HIV-specific CD4 T cells. Spontaneous IL-10 expression, measured as either plasma IL-10 protein or IL-10 mRNA in peripheral blood mononuclear cells (PBMCs), correlated positively with viral load and diminished after successful antiretroviral therapy. IL-10 mRNA levels were up-regulated in multiple PBMC subsets in HIV-infected subjects compared with HIV-negative controls, particularly in T, B, and natural killer (NK) cells, whereas monocytes were a major source of IL-10 mRNA in HIV-infected and -uninfected individuals. These data indicate that multiple cell types contribute to IL-10–mediated immune suppression in the presence of uncontrolled HIV viremia.

scholarly journals T-Cell Gene Therapy in Cancer Immunotherapy: Why It Is No Longer Just CARs on The Road

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1588 ◽  
Author(s):  
Michael D. Crowther ◽  
Inge Marie Svane ◽  
Özcan Met
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cancer Cells ◽  
Cell Types ◽  
Tumour Microenvironment ◽  
Antigen Receptors ◽  
The Road ◽  
Multiple Cell ◽  
On The Road ◽  
Cell Gene

T-cells have a natural ability to fight cancer cells in the tumour microenvironment. Due to thymic selection and tissue-driven immunomodulation, these cancer-fighting T-cells are generally low in number and exhausted. One way to overcome these issues is to genetically alter T-cells to improve their effectiveness. This process can involve introducing a receptor that has high affinity for a tumour antigen, with two promising candidates known as chimeric-antigen receptors (CARs), or T-cell receptors (TCRs) with high tumour specificity. This review focuses on the editing of immune cells to introduce such novel receptors to improve immune responses to cancer. These new receptors redirect T-cells innate killing abilities to the appropriate target on cancer cells. CARs are modified receptors that recognise whole proteins on the surface of cancer cells. They have been shown to be very effective in haematological malignancies but have limited documented efficacy in solid cancers. TCRs recognise internal antigens and therefore enable targeting of a much wider range of antigens. TCRs require major histocompatibility complex (MHC) restriction but novel TCRs may have broader antigen recognition. Moreover, there are multiple cell types which can be used as targets to improve the “off-the-shelf” capabilities of these genetic engineering methods.

scholarly journals Analysis of Major Histocompatibility Complex-Bound HIV Peptides Identified from Various Cell Types Reveals Common Nested Peptides and Novel T Cell Responses

2016 ◽  
Vol 90 (19) ◽  
pp. 8605-8620 ◽  
Author(s):  
Marijana Rucevic ◽  
Georgio Kourjian ◽  
Julie Boucau ◽  
Renata Blatnik ◽  
Wilfredo Garcia Bertran ◽  
...  
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
Immune Responses ◽  
Hiv Infection ◽  
Cell Types ◽  
Cell Responses ◽  
Histocompatibility Complex ◽  
Nested Sets ◽  
Infected Cells ◽  
Hla Molecules

ABSTRACTDespite the critical role of epitope presentation for immune recognition, we still lack a comprehensive definition of HIV peptides presented by HIV-infected cells. Here we identified 107 major histocompatibility complex (MHC)-bound HIV peptides directly from the surface of live HIV-transfected 293T cells, HIV-infected B cells, and primary CD4 T cells expressing a variety of HLAs. The majority of peptides were 8 to 12 amino acids (aa) long and mostly derived from Gag and Pol. The analysis of the total MHC-peptidome and of HLA-A02-bound peptides identified new noncanonical HIV peptides of up to 16 aa that could not be predicted by HLA anchor scanning and revealed an heterogeneous surface peptidome. Nested sets of surface HIV peptides included optimal and extended HIV epitopes and peptides partly overlapping or distinct from known epitopes, revealing new immune responses in HIV-infected persons. Surprisingly, in all three cell types, a majority of Gag peptides derived from p15 rather than from the most immunogenic p24. The cytosolic degradation of peptide precursors in corresponding cells confirmed the generation of identified surface-nested peptides. Cytosolic degradation revealed peptides commonly produced in all cell types and displayed by various HLAs, peptides commonly produced in all cell types and selectively displayed by specific HLAs, and peptides produced in only one cell type. Importantly, we identified areas of proteins leading to common presentations of noncanonical peptides by several cell types with distinct HLAs. These peptides may benefit the design of immunogens, focusing T cell responses on relevant markers of HIV infection in the context of HLA diversity.IMPORTANCEThe recognition of HIV-infected cells by immune T cells relies on the presentation of HIV-derived peptides by diverse HLA molecules at the surface of cells. The landscape of HIV peptides displayed by HIV-infected cells is not well defined. Considering the diversity of HLA molecules in the human population, it is critical for vaccine design to identify HIV peptides that may be displayed despite the HLA diversity. We identified 107 HIV peptides directly from the surface of three cell types infected with HIV. They corresponded to nested sets of HIV peptides of canonical and novel noncanonical lengths not predictable by the presence of HLA anchors. Importantly, we identified areas of HIV proteins leading to presentation of noncanonical peptides by several cell types with distinct HLAs. Including such peptides in vaccine immunogen may help to focus immune responses on common markers of HIV infection in the context of HLA diversity.

scholarly journals Inhibition of EZH2 ameliorates lupus-like disease in MRL/lpr mice

2018 ◽  
Author(s):  
Dallas M. Rohraff ◽  
Ye He ◽  
Evan A. Farkash ◽  
Mark Schonfeld ◽  
Pei-Suen Tsou ◽  
...  
Keyword(s):  
T Cells ◽  
Antibody Production ◽  
Cd4 T Cells ◽  
Renal Involvement ◽  
Disease Onset ◽  
Cell Types ◽  
Expression Levels ◽  
Ezh2 Expression ◽  
Dsdna Antibody ◽  
Multiple Cell

AbstractObjectivesWe previously revealed a role for EZH2 in inducing pro-inflammatory epigenetic changes in lupus CD4+ T cells. In this study, we sought to determine if inhibiting EZH2 ameliorates lupus-like disease in MRL/lpr mice.MethodsEZH2 expression levels in multiple cell types in lupus patients were evaluated using flow cytometry and mRNA expression data. Inhibition of EZH2 in MRL/lpr mice was achieved by DZNep intraperitoneal administration using a preventative and a therapeutic treatment model. Effects of DZNep on animal survival, anti-dsDNA antibody production, proteinuria, renal histopathology, cytokine production, and T and B cell numbers and percentages were assessed.ResultsEZH2 expression levels were increased in whole blood, neutrophils, monocytes, B cells, and CD4+ T cells in lupus patients. In MRL/lpr mice, inhibiting EZH2 with DZNep treatment before or after disease onset improved survival and significantly reduced anti-dsDNA antibody production. DZNep-treated mice displayed a significant reduction in renal involvement, splenomegaly, and lymphadenopathy.Lymphoproliferation and numbers of double-negative T cells were significantly reduced in DZNep treated mice. Concentrations of circulating cytokines and chemokines, including TNF, IFN-γ, CCL2, RANTES/CCL5, IL-10, KC/CXCL1, IL-12, IL-12p40 and MIP-1β/CCL4 were decreased in DZNep treated mice.ConclusionsZH2 is upregulated in multiple cell types in lupus patients. Therapeutic inhibition of EZH2 abrogates lupus-like disease in MRL/lpr mice, suggesting that EZH2 inhibitors may be repurposed as a novel therapeutic option in lupus patients.

scholarly journals Landscape of T Cells Transcriptional and Metabolic Modules During HIV Infection Based on Weighted Gene Co-expression Network Analysis

2021 ◽  
Vol 12 ◽  
Author(s):  
Jianting Xu ◽  
Jiahui Pan ◽  
Xin Liu ◽  
Nan Zhang ◽  
Xinyue Zhang ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
T Cell ◽  
Network Analysis ◽  
Hiv Infection ◽  
Metabolic Pathways ◽  
Cell Types ◽  
Core Gene ◽  
Ppar Signaling ◽  
Immunodeficiency Syndrome

Human immunodeficiency virus (HIV) causes acquired immunodeficiency syndrome (AIDS). HIV infection affects the functions and metabolism of T cells, which may determine the fate of patients; however, the specific pathways activated in different T-cell subtypes (CD4+ and CD8+ T cells) at different stages of infection remain unclear. We obtained transcriptome data of five individuals each with early HIV infection, chronic progressive HIV infection, and no HIV infection. Weighted gene co-expression network analysis was used to evaluate changes in gene expression to determine the antiviral response. An advanced metabolic algorithm was then applied to compare the alterations in metabolic pathways in the two T-cell subtypes at different infection stages. We identified 23 and 20 co-expressed gene modules in CD4+ T and CD8+ T cells, respectively. CD4+ T cells from individuals in the early HIV infection stage were enriched in genes involved in metabolic and infection-related pathways, whereas CD8+ T cells were enriched in genes involved in cell cycle and DNA replication. Three key modules were identified in the network common to the two cell types: NLRP1 modules, RIPK1 modules, and RIPK2 modules. The specific role of NLRP1 in the regulation of HIV infection in the human body remains to be determined. Metabolic functional analysis of the two cells showed that the significantly altered metabolic pathways after HIV infection were valine, leucine, and isoleucine degradation; beta-alanine metabolism; and PPAR signaling pathways. In summary, we found the core gene expression modules and different pathways activated in CD4+ and CD8+ T cells, along with changes in their metabolic pathways during HIV infection progression. These findings can provide an overall resource for establishing biomarkers to facilitate early diagnosis and potential guidance for new targeted therapeutic strategies.

scholarly journals Integrative transcriptomic analysis of SLE reveals IFN-driven cross-talk between immune cells

2020 ◽  
Author(s):  
Bharat Panwar ◽  
Benjamin J. Schmiedel ◽  
Shu Liang ◽  
Brandie White ◽  
Enrique Rodriguez ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
Autoimmune Disease ◽  
Cross Talk ◽  
Immune Cell ◽  
Cell Types ◽  
Cell Populations ◽  
Multiple Cell ◽  
Classical Monocytes ◽  
Multiple Immune Cell

ABSTRACTThe systemic lupus erythematosus (SLE) is an incurable autoimmune disease disproportionately affecting women and may lead to damage in multiple different organs. The marked heterogeneity in its clinical manifestations is a major obstacle in finding targeted treatments and involvement of multiple immune cell types further increases this complexity. Thus, identifying molecular subtypes that best correlate with disease heterogeneity and severity as well as deducing molecular cross-talk among major immune cell types that lead to disease progression are critical steps in the development of more informed therapies for SLE. Here we profile and analyze gene expression of six major circulating immune cell types from patients with well-characterized SLE (classical monocytes (n=64), T cells (n=24), neutrophils (n=24), B cells (n=20), conventional (n=20) and plasmacytoid (n=22) dendritic cells) and from healthy control subjects. Our results show that the interferon (IFN) response signature was the major molecular feature that classified SLE patients into two distinct groups: IFN-signature negative (IFNneg) and positive (IFNpos). We show that the gene expression signature of IFN response was consistent (i) across all immune cell types, (ii) all single cells profiled from three IFNpos donors using single-cell RNA-seq, and (iii) longitudinal samples of the same patient. For a better understanding of molecular differences of IFNpos versus IFNneg patients, we combined differential gene expression analysis with differential Weighted Gene Co-expression Network Analysis (WGCNA), which revealed a relatively small list of genes from classical monocytes including two known immune modulators, one the target of an approved therapeutic for SLE (TNFSF13B/BAFF: belimumab) and one itself a therapeutic for Rheumatoid Arthritis (IL1RN: anakinra). For a more integrative understanding of the cross-talk among different cell types and to identify potentially novel gene or pathway connections, we also developed a novel gene co-expression analysis method for joint analysis of multiple cell types named integrated WGNCA (iWGCNA). This method revealed an interesting cross-talk between T and B cells highlighted by a significant enrichment in the expression of known markers of T follicular helper cells (Tfh), which also correlate with disease severity in the context of IFNpos patients. Interestingly, higher expression of BAFF from all myeloid cells also shows a strong correlation with enrichment in the expression of genes in T cells that may mark circulating Tfh cells or related memory cell populations. These cell types have been shown to promote B cell class-switching and antibody production, which are well-characterized in SLE patients. In summary, we generated a large-scale gene expression dataset from sorted immune cell populations and present a novel computational approach to analyze such data in an integrative fashion in the context of an autoimmune disease. Our results reveal the power of a hypothesis-free and data-driven approach to discover drug targets and reveal novel cross-talk among multiple immune cell types specific to a subset of SLE patients. This approach is immediately useful for studying autoimmune diseases and is applicable in other contexts where gene expression profiling is possible from multiple cell types within the same tissue compartment.

scholarly journals Assessing the co-variability of DNA methylation across peripheral cells and tissues: Implications for the interpretation of findings in epigenetic epidemiology

PLoS Genetics ◽  
2021 ◽  
Vol 17 (3) ◽  
pp. e1009443
Author(s):  
Eilis Hannon ◽  
Georgina Mansell ◽  
Emma Walker ◽  
Marta F. Nabais ◽  
Joe Burrage ◽  
...  
Keyword(s):  
Dna Methylation ◽  
T Cells ◽  
Blood Cell ◽  
Whole Blood ◽  
Association Studies ◽  
Cell Types ◽  
Peripheral Tissues ◽  
Epigenetic Epidemiology ◽  
Blood Cell Type ◽  
Multiple Cell

Most epigenome-wide association studies (EWAS) quantify DNA methylation (DNAm) in peripheral tissues such as whole blood to identify positions in the genome where variation is statistically associated with a trait or exposure. As whole blood comprises a mix of cell types, it is unclear whether trait-associated DNAm variation is specific to an individual cellular population. We collected three peripheral tissues (whole blood, buccal epithelial and nasal epithelial cells) from thirty individuals. Whole blood samples were subsequently processed using fluorescence-activated cell sorting (FACS) to purify five constituent cell-types (monocytes, granulocytes, CD4+ T cells, CD8+ T cells, and B cells). DNAm was profiled in all eight sample-types from each individual using the Illumina EPIC array. We identified significant differences in both the level and variability of DNAm between different sample types, and DNAm data-derived estimates of age and smoking were found to differ dramatically across sample types from the same individual. We found that for the majority of loci variation in DNAm in individual blood cell types was only weakly predictive of variance in DNAm measured in whole blood, although the proportion of variance explained was greater than that explained by either buccal or nasal epithelial samples. Covariation across sample types was much higher for DNAm sites influenced by genetic factors. Overall, we observe that DNAm variation in whole blood is additively influenced by a combination of the major blood cell types. For a subset of sites, however, variable DNAm detected in whole blood can be attributed to variation in a single blood cell type providing potential mechanistic insight about EWAS findings. Our results suggest that associations between whole blood DNAm and traits or exposures reflect differences in multiple cell types and our data will facilitate the interpretation of findings in epigenetic epidemiology.

scholarly journals Alloantigen presentation and graft-versus-host disease: fuel for the fire

Blood ◽  
2016 ◽  
Vol 127 (24) ◽  
pp. 2963-2970 ◽  
Author(s):  
Motoko Koyama ◽  
Geoffrey R. Hill
Keyword(s):  
T Cells ◽  
Graft Versus Host Disease ◽  
Cell Types ◽  
Immunological Tolerance ◽  
Host Disease ◽  
Hematopoietic Malignancies ◽  
Graft Versus Host ◽  
Donor T Cells ◽  
Multiple Cell ◽  
Antigen Presenting

Abstract Allogeneic stem cell transplantation (SCT) is a unique procedure, primarily in patients with hematopoietic malignancies, involving chemoradiotherapy followed by the introduction of donor hematopoietic and immune cells into an inflamed and lymphopenic environment. Interruption of the process by which recipient alloantigen is presented to donor T cells to generate graft-versus-host disease (GVHD) represents an attractive therapeutic strategy to prevent morbidity and mortality after SCT and has been increasingly studied in the last 15 years. However, the immune activation resulting in GVHD has no physiological equivalent in nature; alloantigen is ubiquitous, persists indefinitely, and can be presented by multiple cell types at numerous sites, often on incompatible major histocompatibility complex, and occurs in the context of intense inflammation early after SCT. The recognition that alloantigen presentation is also critical to the development of immunological tolerance via both deletional and regulatory mechanisms further adds to this complexity. Finally, GVHD itself appears capable of inhibiting the presentation of microbiological antigens by donor dendritic cells late after SCT that is mandatory for the establishment of effective pathogen-specific immunity. Here, we review our current understanding of alloantigen, its presentation by various antigen-presenting cells, subsequent recognition by donor T cells, and the potential of therapeutic strategies interrupting this disease-initiating process to modify transplant outcome.

scholarly journals Chimeric immune receptor T cells bypass class I requirements and recognize multiple cell types relevant in HIV-1 infection

Virology ◽  
2003 ◽  
Vol 306 (2) ◽  
pp. 371-375 ◽  
Author(s):  
Michael E Severino ◽  
Phuong Thi Nguyen Sarkis ◽  
Bruce D Walker ◽  
Otto O Yang
Keyword(s):  
T Cells ◽  
Cell Types ◽  
Class I ◽  
Immune Receptor ◽  
Multiple Cell ◽  
Hiv 1

scholarly journals Exaggerated Proinflammatory and Th1 Responses in the Absence of γ/δ T Cells after Infection withListeria monocytogenes

2001 ◽  
Vol 69 (12) ◽  
pp. 7213-7223 ◽  
Author(s):  
Marianne J. Skeen ◽  
Emily P. Rix ◽  
Molly M. Freeman ◽  
H. Kirk Ziegler
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Critical Role ◽  
Cell Types ◽  
T Cell Response ◽  
Response Models ◽  
Multiple Cell ◽  
Ifn Γ ◽  
Precise Role

ABSTRACT While γ/δ T cells are involved in host defense and immunopathology in a variety of infectious diseases, their precise role is not yet clearly defined. In the absence of γ/δ T cells, mice die after infection with a dose of Listeria monocytogenes that is not lethal in immunologically intact animals. Morbidity might result from insufficient levels of cytokines normally produced by γ/δ T cells or conversely from an excess of cytokines due to a lack of down-regulation of the inflammatory response in the absence of γ/δ T cells. Consistent with a regulatory role, we found that systemic levels of proinflammatory cytokines (interleukin-6 [IL-6], IL-12, and gamma interferon [IFN-γ]) were significantly higher in the absence of γ/δ T cells during the innate phase of the response. Using combinations of genetically altered and immunodepleted mice, we found evidence for γ/δ T-cell-mediated regulation of IFN-γ production by multiple cell types of both lymphoid and myeloid lineages. The antigen-specific α/β T-cell response that followed the exaggerated innate response was also increased in γ/δ T-cell-deficient mice. These findings are consistent with an emerging picture from a variety of immune response models of a critical role for γ/δ T cells in down-modulation of the immune response.

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