scholarly journals Diagnostic Biomarkers and Immune Infiltration in Patients With T Cell-Mediated Rejection After Kidney Transplantation

2022 ◽  
Vol 12 ◽  
Author(s):  
Hai Zhou ◽  
Hongcheng Lu ◽  
Li Sun ◽  
Zijie Wang ◽  
Ming Zheng ◽  
...  
Keyword(s):  
T Cells ◽  
Kidney Transplantation ◽  
T Cell ◽  
Immune Cell ◽  
Bioinformatic Analysis ◽  
Genomic Research ◽  
Activated T Cells ◽  
M1 Macrophages ◽  
Diagnostic Biomarkers ◽  
Differently Expressed Genes

T cell-mediated rejection (TCMR) is an important rejection type in kidney transplantation, characterized by T cells and macrophages infiltration. The application of bioinformatic analysis in genomic research has been widely used. In the present study, Microarray data was analyzed to identify the potential diagnostic markers of TCMR in kidney transplantation. Cell-type identification by estimating relative subsets of RNA transcript (CIBERSORT) was performed to determine the distribution of immune cell infiltration in the pathology. Totally 129 upregulated differently expressed genes (DEGs) and 378 downregulated DEGs were identified. The GO and KEGG results demonstrated that DEGs were mainly associated with pathways and diseases involved in immune response. The intersection of the two algorithms (PPI network and LASSO) contains three overlapping genes (CXCR6, CXCL13 and FCGR1A). After verification in GSE69677, only CXCR6 and CXCL13 were selected. Immune cells Infiltration analysis demonstrated that CXCR6 and CXCL13 were positively correlated with gamma delta T cells (p < 0.001), CD4+ memory activated T cells (p < 0.001), CD8+ T cells (p < 0.001) and M1 macrophages (p = 0.006), and negatively correlated with M2 macrophages (p < 0.001) and regulatory T cells (p < 0.001). Immunohistochemical staining and image analysis confirmed the overexpression of CXCR6 and CXCL13 in human allograft TCMR samples. CXCR6 and CXCL13 could be diagnostic biomarkers of TCMR and potential targets for immunotherapy in patients with TCMR.

scholarly journals Prolonged activation of nasal immune cell populations and development of tissue-resident SARS-CoV-2 specific CD8 T cell responses following COVID-19

2021 ◽  
Author(s):  
Anna H.E. Roukens ◽  
Marion König ◽  
Tim Dalebout ◽  
Tamar Tak ◽  
Shohreh Azimi ◽  
...  
Keyword(s):  
T Cells ◽  
Immune System ◽  
T Cell ◽  
Nasal Mucosa ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Upper Airway ◽  
Effector Memory ◽  
Long Term Effects ◽  
Activated T Cells

AbstractThe immune system plays a major role in Coronavirus Disease 2019 (COVID-19) pathogenesis, viral clearance and protection against re-infection. Immune cell dynamics during COVID-19 have been extensively documented in peripheral blood, but remain elusive in the respiratory tract. We performed minimally-invasive nasal curettage and mass cytometry to characterize nasal immune cells of COVID-19 patients during and 5-6 weeks after hospitalization. Contrary to observations in blood, no general T cell depletion at the nasal mucosa could be detected. Instead, we observed increased numbers of nasal granulocytes, monocytes, CD11c+ NK cells and exhausted CD4+ T effector memory cells during acute COVID-19 compared to age-matched healthy controls. These pro-inflammatory responses were found associated with viral load, while neutrophils also negatively correlated with oxygen saturation levels. Cell numbers mostly normalized following convalescence, except for persisting CD127+ granulocytes and activated T cells, including CD38+ CD8+ tissue-resident memory T cells. Moreover, we identified SARS-CoV-2 specific CD8+ T cells in the nasal mucosa in convalescent patients. Thus, COVID-19 has both transient and long-term effects on the immune system in the upper airway.

Recovery of Paired T Cell Receptors from Single-cell Seq-Well Libraries

2019 ◽  
Author(s):  
Ang A. Tu ◽  
Todd M. Gierahn ◽  
Brinda Monian ◽  
Duncan M. Morgan ◽  
Naveen K. Mehta ◽  
...  
Keyword(s):  
T Cells ◽  
Food Allergy ◽  
T Cell ◽  
Single Cell ◽  
T Cell Receptors ◽  
Immune Cell ◽  
Cost Effective ◽  
Antigen Specificity ◽  
Activated T Cells ◽  
Cell Receptors

Abstract High-throughput 3’ single-cell RNA-Sequencing (scRNA-Seq) allows for cost-effective, detailed characterization of thousands of individual immune cells from healthy and diseased tissues. Current techniques, however, are limited in their ability to elucidate essential immune cell features, including the variable sequences of T cell receptors (TCRs) that confer antigen specificity in T cells. Here, we present an enrichment strategy that enables simultaneous analysis of TCR variable sequences and corresponding full transcriptomes from 3’ barcoded scRNA-Seq samples. This approach is compatible with common 3’ scRNA-Seq methods, and adaptable to processed samples post hoc. We applied the technique to resolve clonotype-to-phenotype relationships among antigen-activated T cells from immunized mice and from patients with food allergy. We observed diverse but preferential cellular phenotypes manifest among subsets of expanded clonotypes, including functional Th2 states associated with food allergy. These results demonstrate the utility of our method when studying complex diseases in which clonotype-driven immune responses are critical to understanding the underlying biology.

Association between cetuximab response and differential immunologic gene expression signatures in colorectal cancer metastases.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 558-558 ◽  
Author(s):  
Michael Sangmin Lee ◽  
Benjamin Garrett Vincent ◽  
Autumn Jackson McRee ◽  
Hanna Kelly Sanoff
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
T Cells ◽  
T Cell ◽  
Immune Cell ◽  
Expression Profiles ◽  
Gene Set Enrichment Analysis ◽  
Activated T Cells ◽  
Gene Sets

558 Background: Different immune cell infiltrates into colorectal cancer (CRC) tumors are associated with different prognoses. Tumor-associated macrophages contribute to immune evasion and accelerated tumor progression. Conversely, tumor infiltrating lymphocytes at the invasive margin of CRC liver metastases are associated with improved outcomes with chemotherapy. Cetuximab is an IgG1 monoclonal antibody against epidermal growth factor receptor (EGFR) and stimulates antibody-dependent cellular cytotoxicity (ADCC) in vitro. However, it is unclear in humans if response to cetuximab is modulated by the immune response. We hypothesized that different immune patterns detected in gene expression profiles of CRC metastases are associated with different responses to cetuximab. Methods: We retrieved gene expression data from biopsies of metastases from 80 refractory CRC patients treated with cetuximab monotherapy (GEO GSE5851). Samples were dichotomized by cetuximab response as having either disease control (DC) or progressive disease (PD). We performed gene set enrichment analysis (GSEA) with GenePattern 3.9.4 using gene sets of immunologic signatures obtained from the Molecular Signatures Database v5.0. Results: Among the 68 patients with response annotated, 25 had DC and 43 had PD. In the PD cohort, 59/1910 immunologic gene sets had false discovery rate (FDR) < 0.1. Notably, multiple gene sets upregulated in monocyte signatures were associated with PD. Also, gene sets consistent with PD1-ligated T cells compared to control activated T cells (FDR = 0.052) or IL4-treated CD4 T cells compared to controls (FDR = 0.087) were associated with PD. Conclusions: Cetuximab-resistant patients tended to have baseline increased expression of gene signatures reflective of monocytic infiltrates, consistent with also having increased expression of the IL4-treated T-cell signature. Cetuximab resistance was also associated with increased expression of the PD1-ligated T cell signature. These preliminary findings support further evaluation of the effect of differential immune infiltrates in prognosis of metastatic CRC treated with cetuximab.

6,7,4′-Trihydroxyflavanone Prevents Methamphetamine-Induced T Cell Deactivation by Protecting the Activated T Cells from Apoptosis

2021 ◽  
pp. 1-17
Author(s):  
Hyun-Su Lee ◽  
Gil-Saeng Jeong
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Immune Cell ◽  
Therapeutic Potential ◽  
Cell Activity ◽  
Activated T Cells ◽  
Study Results ◽  
Apoptotic Proteins ◽  
Pre Treatment

Methamphetamine (METH) is an extremely addictive drug that has raised serious public health concerns recently. METH addiction not only results in neuronal cytotoxicity, but it also affects immune cell activity, including T lymphocytes. 6,4,7[Formula: see text]-trihydroxyflavanone (THF), isolated from Dalbergia odorifera, has been studied for its antibacterial activity, but evidence for whether THF has an anti-cytotoxic and protective effect on T cell activation exposed to METH is lacking. In this study, results showed that treatment with THF was not cytotoxic to Jurkat T cells but dose-dependently mitigated the cytotoxicity induced by exposure to METH. The Western blot results demonstrating pre-treatment with THF maintained the expression of anti-apoptotic proteins and phosphorylation of PI3K/Akt/mTOR downregulated by treatment with METH. Furthermore, we found that decreased expression of IL-2 and CD69 by METH exposure was partially restored, and viability was significantly prevented by pre-treatment with THF in activated T cells. These findings were involved in re-elevated expression of anti-apoptotic proteins as well as recovered pathways including MAPK/PI3K/Akt/mTOR in activated T cells pre-exposed to METH. Our results suggest beneficial effects of THF against the cytotoxic and immune-modulating effect of METH on T cells and therapeutic potential of THF for patients with immunodeficiency caused by METH addiction.

scholarly journals Monitoring T Cells Responses Mounted by Therapeutic Cancer Vaccines

2021 ◽  
Vol 8 ◽  
Author(s):  
Kue Peng Lim ◽  
Nur Syafinaz Zainal
Keyword(s):  
Clinical Trials ◽  
T Cells ◽  
T Cell ◽  
Cancer Vaccine ◽  
Cancer Vaccines ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Rapid Development ◽  
Activated T Cells ◽  
Specific Cytotoxicity

With the regulatory approval of Provenge and Talimogene laherparepvec (T-VEC) for the treatment of metastatic prostate cancer and advanced melanoma respectively, and other promising clinical trials outcomes, cancer vaccine is gaining prominence as a cancer therapeutic agent. Cancer vaccine works to induce T cell priming, expansion, and infiltration resulting in antigen-specific cytotoxicity. Such an approach that can drive cytotoxicity within the tumor could complement the success of checkpoint inhibitors as tumors shown to have high immune cell infiltration are those that would respond well to these antibodies. With the advancements in cancer vaccine, methods to monitor and understand how cancer vaccines modify the immune milieu is under rapid development. This includes using ELISpot and intracellular staining to detect cytokine secretion by activated T cells; tetramer and CyTOF to quantitate the level of antigen specific T cells; proliferation and cell killing assay to detect the expansion of T cell and specific killing activity. More recently, T cell profiling has provided unprecedented detail on immune cell subsets and providing clues to the mechanism involved in immune activation. Here, we reviewed cancer vaccines currently in clinical trials and highlight available techniques in monitoring the clinical response in patients.

scholarly journals STAT5 interferes with PD-1 transcriptional activation and affects CD8 + T cell sensitivity to PD-1-dependent immunoregulation

2021 ◽  
Author(s):  
Guanning Wang ◽  
Masaki Tajima ◽  
Tasuku Honjo ◽  
Akio Ohta
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Transcriptional Activation ◽  
Cell Activation ◽  
Cd8 T Cell ◽  
Bioinformatic Analysis ◽  
Fine Tuning ◽  
Target Cells ◽  
Activated T Cells

Abstract Programmed death-1 (PD-1) is a co-inhibitory receptor that dampens immune responses upon the interaction with PD-L1 and PD-L2. Although the PD-1 expression on T cells is known to be activation-dependent, how cytokines modify its regulation is not fully resolved. Using polyclonal T cell activation to study the cytokine-dependent PD-1 regulation, we found that IL-2 inhibited transcriptional upregulation of PD-1 despite the promotion of T cell activation. IL-2-mediated reduction in PD-1 expression augmented CD8 + T cell activities against PD-L1-expressing target cells. To study the mechanism of PD-1 reduction, we focused on STAT5 activation in the IL-2 signaling pathway. Bioinformatic analysis suggested a novel conserved PD-1 promoter domain where NFAT and STAT5 can potentially compete with each other for binding. NFAT1 interaction with this domain revealed substantial potency in PD-1 transcription compared to STAT5A, and STAT5A overexpression could quench NFAT1-dependent PD-1 upregulation in a sequence-specific manner. Chromatin immunoprecipitation analysis of activated T cells showed that IL-2 treatment significantly diminished the binding of NFAT1 and NFAT2 in the hypothesized competition site, while STAT5 binding to the same region was increased. These results raise the possibility that the competition of transcriptional factors might be involved in the fine-tuning of PD-1 expression by cytokines such as IL-2.

scholarly journals Activated T-effector seeds: cultivating atherosclerotic plaque through alternative activation

2019 ◽  
Vol 316 (6) ◽  
pp. H1354-H1365 ◽  
Author(s):  
Maria M. Xu ◽  
Patrick A. Murphy ◽  
Anthony T. Vella
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Immune Cell ◽  
Behavior Pattern ◽  
Adaptive Immune System ◽  
Alternative Activation ◽  
Branch Points ◽  
Activated T Cells

Atherosclerosis is a chronic inflammatory pathology that precipitates substantial morbidity and mortality. Although initiated by physiological patterns of low and disturbed flow that differentially prime endothelial cells at sites of vessel branch points and curvature, the chronic, smoldering inflammation of atherosclerosis is accelerated by comorbidities involving inappropriate activation of the adaptive immune system, such as autoimmunity. The innate contributions to atherosclerosis, especially in the transition of monocyte to lipid-laden macrophage, are well established, but the mechanisms underpinning the infiltration, persistence, and effector dynamics of CD8 T cells in particular are not well understood. Adaptive immunity is centered on a classical cascade of antigen recognition and activation, costimulation, and effector cytokine secretion upon recall of antigen. However, chronic inflammation can generate alternative cues that supplant this behavior pattern and promote the retention and activation of peripherally activated T cells. Furthermore, the atherogenic foci that activated immune cell infiltrate are unique lipid-laden environments that offer a diverse array of stimuli, including those of survival, antigen hyporesponsiveness, and inflammatory cytokine expression. This review will focus on how known cardiovascular comorbidities may be influencing CD8 T-cell activation and how, once infiltrated within atherogenic foci, these T cells face a multitude of cues that skew the classical cascade of T-cell behavior, highlighting alternative modes of activation that may help contextualize associations of autoimmunity, viral infection, and immunotherapy with cardiovascular morbidity.

scholarly journals Functional Evaluation of Activation-dependent Alterations in the Sialoglycan Composition of T Cells

2013 ◽  
Vol 289 (3) ◽  
pp. 1564-1579 ◽  
Author(s):  
Yuko Naito-Matsui ◽  
Shuhei Takada ◽  
Yoshinobu Kano ◽  
Tomonori Iyoda ◽  
Manabu Sugai ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Immune Cell ◽  
Cell Interactions ◽  
Functional Evaluation ◽  
Activated T Cells

Sialic acids (Sias) are often conjugated to the termini of cellular glycans and are key mediators of cellular recognition. Sias are nine-carbon acidic sugars, and, in vertebrates, the major species are N-acetylneuraminic acid (Neu5Ac) and N-glycolylneuraminic acid (Neu5Gc), differing in structure at the C5 position. Previously, we described a positive feedback loop involving regulation of Neu5Gc expression in mouse B cells. In this context, Neu5Gc negatively regulated B-cell proliferation, and Neu5Gc expression was suppressed upon activation. Similarly, resting mouse T cells expressed principally Neu5Gc, and Neu5Ac was induced upon activation. In the present work, we used various probes to examine sialoglycan expression by activated T cells in terms of the Sia species expressed and the linkages of Sias to glycans. Upon T-cell activation, sialoglycan expression shifted from Neu5Gc to Neu5Ac, and the linkage shifted from α2,6 to α2,3. These changes altered the expression levels of sialic acid-binding immunoglobulin-like lectin (siglec) ligands. Expression of sialoadhesin and Siglec-F ligands increased, and that of CD22 ligands decreased. Neu5Gc exerted a negative effect on T-cell activation, both in terms of the proliferative response and in the context of activation marker expression. Suppression of Neu5Gc expression in mouse T and B cells prevented the development of nonspecific CD22-mediated T cell-B cell interactions. Our results suggest that an activation-dependent shift from Neu5Gc to Neu5Ac and replacement of α2,6 by α2,3 linkages may regulate immune cell interactions at several levels.

scholarly journals The Immune Cell Landscape in Renal Allografts

2021 ◽  
Vol 30 ◽  
pp. 096368972199545
Author(s):  
Jun Lu ◽  
Yi Zhang ◽  
Jingjing Sun ◽  
Shulin Huang ◽  
Weizhen Wu ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
T Cell ◽  
Immune Cells ◽  
Immune Cell ◽  
Cell Infiltration ◽  
M1 Macrophages ◽  
Deconvolution Analysis ◽  
Renal Allografts ◽  
Antibody Mediated Rejection

Immune cell infiltration plays an important role in the pathophysiology of kidney grafts, but the composition of immune cells is ill-defined. Here, we aimed at evaluating the levels and composition of infiltrating immune cells in kidney grafts. We used CIBERSORT, an established algorithm, to estimate the proportions of 22 immune cell types based on gene expression profiles. We found that non-rejecting kidney grafts were characteristic with high rates of M2 macrophages and resting mast cells. The proportion of M1 macrophages and activated NK cells were increased in antibody-mediated rejection (ABMR). In T cell-mediated rejection (TCMR), a significant increase in CD8 T cell and γδT cell infiltration was observed. CD8 positive T cells were dramatically increased in mixed-ABMR/TCMR. Then, the function of ABMR and TCMR prognostic molecular biomarkers were identified. Finally, we described the gene expression of molecular markers for ABMR diagnosis was elevated and related to the ratio of monocytes and M1 macrophages in ABMR biopsies, while the expression of TCMR diagnosis markers was increased too and positively correlated with γδT cells and activated CD4 memory T cells in TCMR biopsies. Our data suggest that CIBERSORT’s deconvolution analysis of gene expression data provides valuable information on the composition of immune cells in renal allografts.

scholarly journals Enhanced CD4+ and CD8+ T cell infiltrate within convex hull defined pancreatic islet borders as autoimmune diabetes progresses

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Alexander J. Dwyer ◽  
Jacob M. Ritz ◽  
Jason S. Mitchell ◽  
Tijana Martinov ◽  
Mohannad Alkhatib ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Convex Hull ◽  
Pancreatic Islets ◽  
Immune Cell ◽  
Nod Mice ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Analytical Strategy ◽  
Islet Mass

AbstractThe notion that T cell insulitis increases as type 1 diabetes (T1D) develops is unsurprising, however, the quantitative analysis of CD4+ and CD8+ T cells within the islet mass is complex and limited with standard approaches. Optical microscopy is an important and widely used method to evaluate immune cell infiltration into pancreatic islets of Langerhans for the study of disease progression or therapeutic efficacy in murine T1D. However, the accuracy of this approach is often limited by subjective and potentially biased qualitative assessment of immune cell subsets. In addition, attempts at quantitative measurements require significant time for manual analysis and often involve sophisticated and expensive imaging software. In this study, we developed and illustrate here a streamlined analytical strategy for the rapid, automated and unbiased investigation of islet area and immune cell infiltration within (insulitis) and around (peri-insulitis) pancreatic islets. To this end, we demonstrate swift and accurate detection of islet borders by modeling cross-sectional islet areas with convex polygons (convex hulls) surrounding islet-associated insulin-producing β cell and glucagon-producing α cell fluorescent signals. To accomplish this, we used a macro produced with the freeware software ImageJ equipped with the Fiji Is Just ImageJ (FIJI) image processing package. Our image analysis procedure allows for direct quantification and statistical determination of islet area and infiltration in a reproducible manner, with location-specific data that more accurately reflect islet areas as insulitis proceeds throughout T1D. Using this approach, we quantified the islet area infiltrated with CD4+ and CD8+ T cells allowing statistical comparison between different age groups of non-obese diabetic (NOD) mice progressing towards T1D. We found significantly more CD4+ and CD8+ T cells infiltrating the convex hull-defined islet mass of 13-week-old non-diabetic and 17-week-old diabetic NOD mice compared to 4-week-old NOD mice. We also determined a significant and measurable loss of islet mass in mice that developed T1D. This approach will be helpful for the location-dependent quantitative calculation of islet mass and cellular infiltration during T1D pathogenesis and can be combined with other markers of inflammation or activation in future studies.

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