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Quantitative proteomic analyses of CD4+ and CD8+ T cells reveals differentially expressed proteins in multiple sclerosis patients and healthy controls

ABSTRACT: We characterize the proteome from CD4+ and CD8+ T cells form multiple sclerosis (MS) patients and from healthy controls (K) by mass spectrometry-based label-free quantitative proteomics for biomarker discovery.

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Culture Condition:cd4+ Cell, Culture Condition:cd8+ Cell

DISEASE(S): Multiple Sclerosis

SUBMITTER: Tone Berge

LAB HEAD: Tone Berge

PROVIDER: PXD011785 | Pride | 2019-08-22

REPOSITORIES: Pride

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			Action	DRS
	CD4_K004.raw	Raw
	CD4_K005.raw	Raw
	CD4_K006.raw	Raw
	CD4_K007__2.raw	Raw
	CD4_K008.raw	Raw

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Publications

Quantitative proteomic analyses of CD4<sup>+</sup> and CD8<sup>+</sup> T cells reveal differentially expressed proteins in multiple sclerosis patients and healthy controls.

Berge Tone T Eriksson Anna A Brorson Ina Skaara IS Høgestøl Einar August EA Berg-Hansen Pål P Døskeland Anne A Mjaavatten Olav O Bos Steffan Daniel SD Harbo Hanne F HF Berven Frode F

Clinical proteomics 20190508

<h4>Background</h4>Multiple sclerosis (MS) is an autoimmune, neuroinflammatory disease, with an unclear etiology. However, T cells play a central role in the pathogenesis by crossing the blood-brain-barrier, leading to inflammation of the central nervous system and demyelination of the protective sheath surrounding the nerve fibers. MS has a complex inheritance pattern, and several studies indicate that gene interactions with environmental factors contribute to disease onset.<h4>Methods</h4>In t ...[more]

PMID: 31080378

Similar Datasets

Quantitative proteomic analyses of CD4<sup>+</sup> and CD8<sup>+</sup> T cells reveal differentially expressed proteins in multiple sclerosis patients and healthy controls.

Project description:BackgroundMultiple sclerosis (MS) is an autoimmune, neuroinflammatory disease, with an unclear etiology. However, T cells play a central role in the pathogenesis by crossing the blood-brain-barrier, leading to inflammation of the central nervous system and demyelination of the protective sheath surrounding the nerve fibers. MS has a complex inheritance pattern, and several studies indicate that gene interactions with environmental factors contribute to disease onset.MethodsIn the current study, we evaluated T cell dysregulation at the protein level using electrospray liquid chromatography-tandem mass spectrometry to get novel insights into immune-cell processes in MS. We have analyzed the proteomic profiles of CD4+ and CD8+ T cells purified from whole blood from 13 newly diagnosed, treatment-naive female patients with relapsing-remitting MS and 14 age- and sex-matched healthy controls.ResultsAn overall higher protein abundance was observed in both CD4+ and CD8+ T cells from MS patients when compared to healthy controls. The differentially expressed proteins were enriched for T-cell specific activation pathways, especially CTLA4 and CD28 signaling in CD4+ T cells. When selectively analyzing proteins expressed from the genes most proximal to > 200 non-HLA MS susceptibility polymorphisms, we observed differential expression of eight proteins in T cells between MS patients and healthy controls, and there was a correlation between the genotype at three MS genetic risk loci and protein expressed from proximal genes.ConclusionOur study provides evidence for proteomic differences in T cells from relapsing-remitting MS patients compared to healthy controls and also identifies dysregulation of proteins encoded from MS susceptibility genes.

| S-EPMC6505067 | biostudies-literature

CD8<sup>+</sup> T cell gene expression analysis identifies differentially expressed genes between multiple sclerosis patients and healthy controls.

Project description:BackgroundGenetic and clinical observations have indicated T cells are involved in MS pathology. There is little insight in how T cells are involved and whether or not these can be used as markers for MS.ObjectivesAnalysis of the gene expression profiles of circulating CD8+ T cells of MS patients compared to healthy controls.MethodsRNA from purified CD8+ T cells was sequenced and analyzed for differential gene expression. Pathway analyses of genes at several p-value cutoffs were performed to identify putative pathways involved.ResultsWe identified 36 genes with significant differential gene expression in MS patients. Four genes reached at least 2-fold differences in expression. The majority of differentially expressed genes was higher expressed in MS patients. Genes associated to MS in GWAS showed enrichment amongst the differentially expressed genes. We did not identify enrichment of specific pathways amongst the differentially expressed genes in MS patients.ConclusionsCD8+ T cells of MS patients show differential gene expression, with predominantly higher activity of genes in MS patients. We do not identify specific biological pathways in our study. More detailed analysis of CD8+ T cells and subtypes of these may increase understanding of how T cells are involved in MS.

| S-EPMC7731718 | biostudies-literature

Hmga1 is differentially expressed and mediates silencing of the CD4/CD8 loci in T cell lineages and leukemic cells.

Project description:High-mobility group A1 (Hmga1) protein is an architectural chromatin factor, and aberrant Hmga1 expression in mice causes hematopoietic malignancies with defects in cellular differentiation. However, the functional involvement of Hmga1 in hematopoietic development and leukemic cells remains to be elucidated. Using Hmga1-green fluorescent protein (GFP) knock-in mice that endogenously express an Hmga1-GFP fusion protein, we examined Hmga1 expression in undifferentiated and differentiated populations of hematopoietic cells. During early T cell development in the thymus, Hmga1 is highly expressed in CD4/CD8-double negative (DN) cells and is transiently downregulated in CD4/CD8-double positive (DP) cells. Consistently, Hmga1 directly binds to cis-regulatory elements in the CD4/CD8 loci and the heterochromatin foci in DN-stage cells, but not in DP cells. Interestingly, CD4/CD8 expression in DN-stage leukemic cells is induced by inhibition of Hmga1 binding to nuclear DNA or RNA interference-mediated Hmga1 knockdown. In addition, Hmga1-depleted leukemic T cells markedly diminish proliferation, with transcriptional activation of cyclin-dependent kinase inhibitor genes as a direct target of Hmga1. The data in the present study reveal a role of Hmga1 in transcriptional silencing in T cell lineages and leukemic cells.

| S-EPMC7713622 | biostudies-literature

Differentially expressed genes between systemic sclerosis and rheumatoid arthritis.

Project description:BackgroundEvidence is accumulating to characterise the key differences between systemic sclerosis (SSc) and rheumatoid arthritis (RA), which are similar but distinct systemic autoimmune diseases. However, the differences at the genetic level are not yet clear. Therefore, the aim of the present study was to identify key differential genes between patients with SSc and RA.MethodsThe Gene Expression Omnibus database was used to identify differentially expressed genes (DEGs) between SSc and RA biopsies. The DEGs were then functionally annotated using Gene Ontology (GO) terms and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways with the Database for Annotation, Visualization and Integrated Discovery (DAVID) tools. A protein-protein interaction (PPI) network was constructed with Cytoscape software. The Molecular Complex Detection (MCODE) plugin was also used to evaluate the biological importance of the constructed gene modules.ResultsA total of 13,556 DEGs were identified between the five SSc patients and seven RA patients, including 13,465 up-regulated genes and 91 down-regulated genes. Interestingly, the most significantly enriched GO terms of up- and down-regulated genes were related to extracellular involvement and immune activity, respectively, and the top six highly enriched KEGG pathways were related to the same processes. In the PPI network, the top 10 hub nodes and top four modules harboured the most relevant genes contributing to the differences between SSc and RA, including key genes such as IL6, EGF, JUN, FGF2, BMP2, FOS, BMP4, LRRK2, CTNNB1, EP300, CD79, and CXCL13.ConclusionsThese genes such as IL6, EGF, JUN, FGF2, BMP2, FOS, BMP4, LRRK2, CTNNB1, EP300, CD79, and CXCL13 can serve as new targets for focused research on the distinct molecular pathogenesis of SSc and RA. Furthermore, these genes could serve as potential biomarkers for differential diagnoses or therapeutic targets for treatment.

| S-EPMC6549285 | biostudies-literature

STING differentially regulates experimental GVHD mediated by CD8 versus CD4 T cell subsets.

Project description:The stimulator of interferon genes (STING) pathway has been proposed as a key regulator of gastrointestinal homeostasis and inflammatory responses. Although STING reportedly protects against gut barrier damage and graft-versus-host disease (GVHD) after major histocompatibility complex (MHC)-mismatched allogeneic hematopoietic stem cell transplantation (aHSCT), its effect in clinically relevant MHC-matched aHSCT is unknown. Studies here demonstrate that STING signaling in nonhematopoietic cells promoted MHC-matched aHSCT-induced GVHD and that STING agonists increased type I interferon and MHC I expression in nonhematopoietic mouse intestinal organoid cultures. Moreover, mice expressing a human STING allele containing three single-nucleotide polymorphisms associated with decreased STING activity also developed reduced MHC-matched GVHD, demonstrating STING's potential clinical importance. STING-/- recipients experienced reduced GVHD with transplant of purified donor CD8+ T cells in both MHC-matched and MHC-mismatched models, reconciling the seemingly disparate results. Further examination revealed that STING deficiency reduced the activation of donor CD8+ T cells early after transplant and promoted recipient MHC class II+ antigen-presenting cell (APC) survival. Therefore, APC persistence in STING pathway absence may account for the increased GVHD mediated by CD4+ T cells in completely mismatched recipients. In total, our findings have important implications for regulating clinical GVHD by targeting STING early after aHSCT and demonstrate that an innate immune pathway has opposing effects on the outcome of aHSCT, depending on the donor/recipient MHC disparity.

| S-EPMC7392054 | biostudies-literature

Clonal composition of neuroantigen-specific CD8+ and CD4+ T-cells in multiple sclerosis.

Project description:Patients with multiple sclerosis (MS) show a high prevalence of myelin-reactive CD8+ and CD4+ T-cell responses, which are the putative effectors/modulators of CNS neuropathology. Utilizing a novel combination of short-term culture, CFSE-based sorting and anchored PCR, we evaluated clonal compositions of neuroantigen-targeting T-cells from RRMS patients and controls. CDR3 region analysis of TCR? chains revealed biased use of specific TCRBV-bearing CD4+ clones. CD8+ clones showed homology to published TCR from CNS-infiltrating T-cells in MS lesions. These studies are the first description of TCR usage of CNS-specific CD8+ T-cells and provide insights into their potential regulatory role in disease.

| S-EPMC3092854 | biostudies-literature

Characterization of Differentially Expressed Circulating miRNAs in Metabolically Healthy versus Unhealthy Obesity.

Project description:Obese individuals without metabolic comorbidities are categorized as metabolically healthy obese (MHO). MicroRNAs (miRNAs) may be implicated in MHO. This cross-sectional study explores the link between circulating miRNAs and the main components of metabolic syndrome (MetS) in the context of obesity. We also examine oxidative stress biomarkers in MHO vs. metabolically unhealthy obesity (MUO). We analysed 3536 serum miRNAs in 20 middle-aged obese individuals: 10 MHO and 10 MUO. A total of 159 miRNAs were differentially expressed, of which, 72 miRNAs (45.2%) were higher and 87 miRNAs (54.7%) were lower in the MUO group. In addition, miRNAs related to insulin signalling and lipid metabolism pathways were upregulated in the MUO group. Among these miRNAs, hsa-miR-6796-5p and hsa-miR-4697-3p, which regulate oxidative stress, showed significant correlations with glucose, triglycerides, HbA1c and HDLc. Our results provide evidence of a pattern of differentially expressed miRNAs in obesity according to MetS, and identify those related to insulin resistance and lipid metabolism pathways.

| S-EPMC8004231 | biostudies-literature

Identification of Monotonically Differentially Expressed Genes for IFN-β-Treated Multiple Sclerosis Patients.

Project description:Multiple sclerosis (MS) is a common neurological disability of the central nervous system. Immune-modulatory therapy with interferon-β (IFN-β) has been used as a first-line treatment to prevent relapses in MS patients. While the therapeutic mechanism of IFN-β has not been fully elucidated, the data of microarray experiments that collected longitudinal gene expression profiles to evaluate the long-term response of IFN-β treatment have been analyzed using statistical methods that were incapable of dealing with such data. In this study, the GeneRank method was applied to generate weighted gene expression values and the monotonically expressed genes (MEGs) for both IFN-β treatment responders and nonresponders were identified. The proposed procedure identified 13 MEGs for the responders and 2 MEGs for the nonresponders, most of which are biologically relevant to MS. Our work here provides some useful insight into the mechanism of IFN-β treatment for MS patients. A full understanding of the therapeutic mechanism will enable a more personalized treatment strategy possible.

| S-EPMC6930778 | biostudies-literature

Population specific reference ranges of CD3, CD4 and CD8 lymphocyte subsets among healthy Kenyans.

Project description:BACKGROUND: The enumeration of absolute CD4 counts is of primary importance for many medical conditions especially HIV infection where therapeutic initiation depends on the count. These ranges tend to vary across populations. However, these ranges have not been comprehensively established in the Kenyan population. Therefore, this study aimed at establishing the reference ranges for the CD4 and CD8 T-lymphocytes in normal healthy individuals in Kenya. METHODS: A total of 315 individuals of the ages between 16 and 60 years old, in 5 different regions of the country, were recruited into the study. They were screened for diseases that potentially cause lymphocyte homeostasis perturbation. CD4/CD8 Counts were performed by use of a FACSCalibur flow cytometer (Becton-Dickinson, NJ) equipped with automated acquisition and analysis software. Results were analysed according to age, sex and region. RESULTS: Results were presented as means and ranges (in parenthesis) generated non parametrically as 2.5 and 97.5 percentiles as follows; In general population; CD3 1655 (614-2685 cells/?L ), CD4 920 (343-1493 cells/?L), and CD8 646 (187-1139 cells/?L), while according to sex, females; CD3 1787 (697-2841 cells/?L), CD4 1010 (422-1572 cells/?L), CD8 659 (187-1180 cells/?L); males; CD3 1610 (581-2641 cells/?L), CD4 889(320-1459 cells/?L) and CD8 644 (185-1140 cells/?L). The general reference ranges for CD4/CD8 ratios were as follows; general population 1.57(0.50-2.74), males 1.51(0.49-2.64) and females 1.69(0.55-2.95). CONCLUSION: The lymphocyte reference ranges for the Kenyan population are fairly comparable to those established in other African populations. The ranges also differ appreciably from those established in Germany, Italy and Switzerland. Furthermore, the study reported significant differences in the ranges of different population clusters within Kenya, as well us between males and females.

| S-EPMC3827884 | biostudies-other

IL-2R? abundance differentially tunes IL-2 signaling dynamics in CD4+ and CD8+ T cells.

Project description:Interleukin-2 (IL-2) stimulates both activated CD4+ and CD8+ T cells to proliferate. IL-2 signals through an identical receptor complex and promotes the same dose-dependent phosphorylation of the canonical transcription factor STAT5 in both cell types. Despite this, CD8+ T cells enter the S phase earlier and proliferate to a greater extent than do CD4+ T cells in response to IL-2. We identified distinct IL-2 signaling dynamics in CD4+ and CD8+ T cells. In IL-2-stimulated CD8+ T cells, STAT5 phosphorylation increased rapidly and was sustained for 6 hours. In contrast, CD4+ T cells had a biphasic response, with maxima at 15 min and 2 to 4 hours after stimulation. Both cell types required vesicular trafficking, but only CD4+ T cells required new protein synthesis to maintain high phosphorylation of STAT5. Two subunits of the IL-2 receptor, IL-2R? and IL-2R?, were twice as abundant in CD8+ T cells than in CD4+ T cells. Reduction of IL-2R? abundance by 50% was sufficient to convert CD8+ T cells to a CD4+ T cell-like signaling pattern and delay S phase entry. These results suggest that the larger pool of IL-2R? chains in CD8+ T cells is required to sustain IL-2 signaling and contributes to the quantitatively greater proliferative response to IL-2 relative to that of CD4+ T cells. This cell type-specific difference in IL-2R? abundance appears to tune responses, potentially preventing extensive, autoimmune proliferation of CD4+ T cells, while still enabling sufficient proliferation of CD8+ T cells to control viral infections.

| S-EPMC5741096 | biostudies-literature

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