scholarly journals THE ROLE OF PREGNANCY-SPECIFIC GLYCOPROTEIN IN REGULATION OF MOLECULAR GENETIC DIFFERENTIATION MECHANISMS OF IMMUNE MEMORY T CELLS

2019 ◽  
Vol 21 (1) ◽  
pp. 49-58 ◽  
Author(s):  
M. B. Rayev ◽  
L. S. Litvinova ◽  
K. A. Yurova ◽  
O. G. Khaziakhmatova ◽  
V. P. Timganova ◽  
...  
Keyword(s):  
T Cells ◽  
Alternative Splicing ◽  
T Cell ◽  
Peripheral Blood ◽  
Functional Activity ◽  
Memory T Cells ◽  
Molecular Genetic ◽  
Immune Memory ◽  
Memory T Cell

The role of pregnancy-specific β1-glycoprotein (PSG) in the regulation of molecular genetic factors determining the functional activity of naїve T cells and T cells of immune memoryin vitrowas studied. Human PSG was isolated with a proprietary immuno-purification method using a biospecific sorbent followed by removing of immunoglobulin contamination with a HiTrapTMProtein G HP column. Physiological concentrations of PSG were used in the experiments. They corresponded to PSG levels in the peripheral blood of pregnant woman: 1, 10 and 100 μg/ml (I, II, III trimester, respectively). The objects of study were monocultures of naїve T cells (CD45RA+) and memory T cells (CD45R0+), obtained by immunomagnetic separation from the peripheral blood of women of reproductive age.It was established that at the level of naїve T cells (CD45RA+) PSG inhibited the expression of CD28 (1, 10, 100 μg/ml) and CD25 (100 μg/ml), without affecting the interleukin-2 (IL-2) production by these cells. At the same time, PSG in all concentrations studied suppressed the expression of CD25 at the immune memory T-cell (CD45R0+) surface but increased the IL-2 production. Expression ofU2af1l4, Gfi1, hnRNPLLgenes regulating the alternative splicing of the Ptprc gene encoding CD45 was also evaluated. It was found, that PSG reduced the expression of theGfi1(1, 10, 100 μg/ml),hnRNPLL(10, 100 μg/ml) genes, but increased the expression of theU2af1l4gene (1, 10, 100 μg/ml) in the naїve T cells. It was shown that at the immune memory T-cells’ level the effects were similar, with PSG rendering them in all concentrations used. The revealed changes in the mRNA transcription ofU2af1l4,Gfi1andhnRNPLLgenes in the studied T cell subsets may lead to the inhibition of CD45 “mature” isoform formation – CD45R0.Thus, PSG reduces the functional activity of naїve T cells and immune memory T cells associated with the expression of costimulation/activation molecules CD25 and CD28 and is involved in the regulation ofPtprcgene alternative splicing, which determines the ratio of CD45 molecule variants. Apparently, using these mechanisms, PSG regulates the functional activity of the memory T cell circulating pool, which is potentially capable of carrying out antigen-specific cytotoxic reactions against fetal antigens in vivo. In general, the data obtained broadens the notion of the PSG role in the regulation of molecular-genetic mechanisms of naїve T cells and immune memory T cells differentiation.

High Numbers Of Memory T Cells Are Associated With Higher Risk Of Grade II-IV Acute Gvhd After Human Allogeneic Transplantation

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2061-2061
Author(s):  
Michael Loschi ◽  
Régis Peffault de Latour ◽  
Raphael Porcher ◽  
Valerie Vanneaux ◽  
Marie Robin ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Multivariate Analysis ◽  
T Cell ◽  
Peripheral Blood ◽  
Acute Gvhd ◽  
Memory T Cells ◽  
Cytotoxic Lymphocytes ◽  
Memory T Cell ◽  
Grade Ii

Abstract Introduction Acute graft versus host disease is a frequent and life threatening complication following HSCT. Some predictive factors have been identified in the last decades. Experimental studies in mice suggest that the naïve cytotoxic T cells (CD3+/CD8+/CD45RA+/CD62L+) are the major mediators of acute GVHD and that removing this subset of the donor T cells, called ‘naïve T cells’, before transplant may reduce the frequency and intensity of GVHD. Detailed immunophenotyping of the graft including naïve and memory (CD3+/CD8+/CD45RA-/CD62L- ; CD3+/CD8+/CD45RA+/CD62L- ; CD3+/CD8+/CD45RA-/CD62L+ ) T-cell contents have never been explored in human GVHD. We studied the correlation between memory and naive T cell in bone marrow and peripheral blood grafts and development of acute GVHD after hematopoietic stem cell transplant. Methods We analyzed by detailed immunophenotyping, the grafts of a cohort of 210 patients among 402 patients who received an allogeneic stem cell transplantation from bone marrow and peripheral blood between January 2009 and June 2012 at a single center. There were no differences between the 210 studied patients and the other 192 in whom grafts were not studied. Characteristics of patients investigated for naïve and memory T cells were compared using Wilcoxon rank-sum tests and Fisher’s exact tests. The main outcome was occurrence of acute GVHD grade II – IV. Cumulating incidence of acute GVHD was estimated using usual methods and compared according to tertiles of T cytotoxic lymphocytes subpopulations using Gray’s test. Adjusted analyses were performed using Fine- Gray proportional hazards models. All tests were two - sided and p-values ≤ 0.05 were considered as indicating significant association. T cytotoxic lymphocytes were typed in all 210 grafts using CD3, CD8, CD45 RA and CD62L four colors immuphenotyping. Clinical and histological characteristics of patients were recorded. Including age, gender, ABO group and rhesus, viral serology of both the donor and the patient, characteristic of the grafts including HLA compatibility, bone marrow or peripheral blood, lymphocytes and nucleated cell and CD34 numeration, conditioning regimens, GVHD prophylaxis, characteristics of GVHD (date of onset, organs involved, stage and grade). Results Median follow up from transplant was 18 months. Cumulative incidence of acute GVHD was 59% (95% CI range 45 to 59) overall, and 49% (95% CI 42 to 56) at 100 days. In univariate analysis increased absolute counts of memory T cell subtypes were significantly correlated with the onset of an acute GVHD grade II – IV. Risk factors for acute GVHD (multivariate analysis) were use of an unrelated donor, positive CMV donor for a negative recipient, and use of TBI 12Gy. In a multivariate analysis the subtype CD3+/CD8+/CD45 RA-/CD62L- was associated with the onset of acute GVHD grade II-IV (adjusted Hazard Ratio = 1.26 and 1.98, p=0.02). Adjusting analysis on the total number of total nucleated cells infused did not affect the results. Restricting analyses to patients receiving peripheral blood stem cells also provided same conclusions. Conclusion This first study on the relation between rate of memory T cell and GVHD revealed that CD3+/CD8+/CD45 RA-/CD62 L- T-cells numbers and percentage were associated with acute GVHD grade II – IV. In contrast to murine models we did not find evidence for a link between naïve T-cells and GVHD risk Disclosures: Robin: novartis: Research Funding.

scholarly journals Influence of age on functional memory T cell diversity

2021 ◽  
Author(s):  
Fengqin Fang ◽  
Wenqiang Cao ◽  
Weikang Zhu ◽  
Nora Lam ◽  
Lingjie Li ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Memory T Cells ◽  
Cell Subset ◽  
Surrogate Marker ◽  
T Cell Subsets ◽  
Immune Memory ◽  
Effector Memory ◽  
Memory T Cell ◽  
Cd73 Expression

Memory T cells exhibit considerable diversity that determines their ability to be protective and their durability. Here, we examined whether changes in T cell heterogeneity contribute to the age-associated failure of immune memory. By screening for age-dependent T cell surface markers, we have identified CD4 and CD8 memory T cell subsets that are unrelated to previously defined subsets of central and effector memory cells. Memory T cells expressing the ecto-5′-nucleotidase CD73 constitute a functionally distinct subset of memory T cells that declines with age. They exhibit many features favorable for immune protection, including longevity and polyfunctionality. They have a low turnover, but are poised to display effector functions and to develop into cells resembling tissue-resident memory T cells (TRM). Upstream regulators of differential chromatin accessibility and transcriptomes include transcription factors that are characteristic for conferring these superior memory features as well as facilitating CD73 expression. CD73 is not just a surrogate marker of these regulatory networks but is directly involved in T cell survival and TRM differentiation Interventions preventing the decline of this T cell subset or increasing CD73 expression have the potential to improve immune memory in older adults.

Role of α-Fetoprotein in Regulation of Proliferation and Functional Activity of Naïve T Cells and Immune Memory T Cells

2019 ◽  
Vol 167 (4) ◽  
pp. 470-474
Author(s):  
S. A. Zamorina ◽  
L. S. Litvinova ◽  
K. A. Yurova ◽  
O. G. Khaziakhmatova ◽  
V. P. Timganova ◽  
...  
Keyword(s):  
T Cells ◽  
Functional Activity ◽  
Memory T Cells ◽  
Immune Memory ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
Regulation Of Proliferation

scholarly journals OP0337 DIFFERENTIAL METHYLATION OF PERIPHERAL BLOOD ADAPTIVE IMMUNE CELLS IN INDIVIDUALS AT HIGH RISK FOR RA AND WITH EARLY RA COMPARED WITH CONTROLS IDENTIFIES PATHWAYS IMPORTANT IN TRANSITION TO ARTHRITIS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 207.2-207
Author(s):  
R. Ai ◽  
D. Boyle ◽  
D. Hammaker ◽  
K. Deane ◽  
V. M. Holers ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Peripheral Blood ◽  
Memory T Cells ◽  
Research Support ◽  
Memory T Cell ◽  
Naïve T Cell ◽  
Naive T Cell

Background:The “Targeting Immune Responses for Prevention of RA” (TIP-RA) collaboration studies individuals at high risk for developing RA because of serum anti-citrullinated protein antibody positivity in absence of arthritis, and is focused on defining how they transition from at-risk to classifiable disease. One potential mechanism is through alterations in epigenetics patterns in adaptive immune cells.Objectives:Previous studies showed that DNA methylation patterns of early RA (ERA) synoviocytes differ from long-standing RA, suggesting that abnormal methylation occurs early in synovium and evolves over time. To extend these observations, we performed a cross-sectional analysis in TIP-RA of DNA methylation signatures in peripheral blood cells in ERA, at-risk anti-CCP3+ individuals and demographically matched CCP- controls.Methods:Genomic DNA was isolated from two independent cohorts of CCP- (cohorts 1 and 2, respectively: B cell: n = 17/34; memory T cell: n = 21/34; and naïve T cell: n = 21/33), CCP3+ (B cell: n = 18/37; memory T cell: n = 20/36; and naïve T cell: n = 20/35), and CCP3+ ERA (B cell: n = 4/18; memory T cell: n = 5/18; and naïve T cell: n = 5/18) after separating PBMCs using antibodies and magnetic beads. Methylation was measured by Illumina Infinium MethylationEPIC chip. Differentially methylated loci (DMLs) were identified using Welch’s t-test and mapped to gene promoter regions to define DM genes (DMGs). Principal component analysis (PCA) was used to represent relationship among groups. Pathway analysis was applied by Reactome.Results:For the initial cohort, 1494, 1097 and 1330 DMLs were identified among CCP+, CCP- and ERA in B cells, memory T cells and naïve T cells, respectively. For the confirmatory cohort, 523, 793 and 548 DMLs were found in corresponding cell populations. The DML overlap between the 2 cohorts was highly significant (p= 2.48E-77). The DMLs were combined for both groups and corresponded to 411, 412, and 351 DMGs in B cells, memory T cells and naïve T cells. Of these, we found 246, 198 and 195 DMGs between CCP3+ and ERA in each peripheral blood cell population, respectively. PCA showed separation of CCP+, CCP- and ERA in each of the three blood cell types by DMLs (Fig. 1). DMGs were mapped to biological pathways to identify DM pathways. Although most were not significant, there were several highly significant differences comparing CCP+, ERA and CCP- in memory T cells involving pathways, including “Interferon gamma signaling” (FDR 7.48E-14), “PD-1 signaling” (FDR 8.71E-10), “Translocation of ZAP-70 to Immunological synapse” (FDR 4.75E-10), and “Phosphorylation of CD3 and TCR zeta chains” (FDR 8.71E-10).Figure 1.PCA shows the separation of CCP+, CCP- and ERA patients in memory T cells in confirmatory cohort.Conclusion:We identified reproducible methylation signatures of CCP-, CCP+, and ERA in peripheral blood B cells, memory T cells and naïve T cells in initial and confirmatory cohorts. The methylome of ERA also demonstrated a distinctive pattern from CCP+, indicating that progression to RA is accompanied by epigenetic remodeling, especially in T cell signaling and interferon responses. These signatures identify critical pathways in CCP positivity and classifiable RA and could provide the basis of novel interventions to prevent disease.Disclosure of Interests:Rizi Ai: None declared, David Boyle: None declared, Deepa Hammaker: None declared, Kevin Deane Grant/research support from: Janssen, Consultant of: Inova, ThermoFisher, Janseen, BMS and Microdrop, V. Michael Holers Grant/research support from: Janssen, Celgene, and BMS, Andre Matti: None declared, William Robinson: None declared, Jane Buckner Grant/research support from: Bristol-Myers Squibb, Janssen, Navin Rao Shareholder of: Janssen Pharmaceuticals, Employee of: Janssen Pharmaceuticals, Frederic Baribaud Shareholder of: Janssen Research & Development, LLC, Employee of: Janssen Research & Development, LLC, Alyssa Johnsen Employee of: Janssen, Sunil Nagpal Shareholder of: Janssen Pharmaceuticals, Employee of: Janssen Pharmaceuticals, Wei Wang: None declared, Gary Firestein Grant/research support from: Lilly, Janssen, Abbvie

scholarly journals Detection of IFNγ-Secreting CD4+ and CD8+ Memory T Cells in COVID-19 Convalescents after Stimulation of Peripheral Blood Mononuclear Cells with Live SARS-CoV-2

Viruses ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1490
Author(s):  
Victoria Matyushenko ◽  
Irina Isakova-Sivak ◽  
Igor Kudryavtsev ◽  
Arina Goshina ◽  
Anna Chistyakova ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Memory T Cells ◽  
Natural Infection ◽  
Intracellular Cytokine Staining ◽  
T Cell Responses ◽  
Effector Memory ◽  
Memory T Cell ◽  
Cell Responses ◽  
Stimulation Of

Background: New coronavirus SARS-CoV-2, a causative agent of the COVID-19 pandemic, has been circulating among humans since November 2019. Multiple studies have assessed the qualitative and quantitative characteristics of virus-specific immunity in COVID-19 convalescents, however, some aspects of the development of memory T-cell responses after natural SARS-CoV-2 infection remain uncovered. Methods: In most of published studies T-cell immunity to the new coronavirus is assessed using peptides corresponding to SARS-CoV-1 or SARS-CoV-2 T-cell epitopes, or with peptide pools covering various parts of the viral proteins. Here, we determined the level of CD4+ and CD8+ memory T-cell responses in COVID-19 convalescents by stimulating PBMCs collected 1 to 6 months after recovery with sucrose gradient-purified live SARS-CoV-2. IFNγ production by the central and effector memory helper and cytotoxic T cells was assessed by intracellular cytokine staining assay and flow cytometry. Results: Stimulation of PBMCs with live SARS-CoV-2 revealed IFNγ-producing T-helper effector memory cells with CD4+CD45RA−CCR7− phenotype, which persisted in circulation for up to 6 month after COVID-19. In contrast, SARS-CoV-2-specific IFNγ-secreting cytotoxic effector memory T cells were found at significant levels only shortly after the disease, but rapidly decreased over time. Conclusion: The stimulation of immune cells with live SARS-CoV-2 revealed a rapid decline in the pool of effector memory CD8+, but not CD4+, T cells after recovery from COVID-19. These data provide additional information on the development and persistence of cellular immune responses after natural infection, and can inform further development of T cell-based SARS-CoV-2 vaccines.

scholarly journals VitaminD3 Regulates T Cell Immune Responses in Allergen and Rhinovirus Induced Asthma

2021 ◽  
Author(s):  
Susetta Finotto ◽  
Patricia Haag ◽  
Darja Andreev ◽  
Nina Li ◽  
Alexander Kiefer ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Murine Model ◽  
Peripheral Blood ◽  
Serum Levels ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Asthmatic Children ◽  
Rhinovirus Infection

Abstract Background: Serum 25(OH)-Vitamin D3 (VitD3) deficiency during infancy has been associated with asthma. The potential therapeutic role of VitD3 given in the airways and its interference with the allergen and Rhinovirus was the objective of this study. Methods: In two cohorts of children with and without asthma, serum levels of the C-reactive protein (CRP) were correlated to Serum VitD3 and in peripheral blood T cell inhibitor marker Programmed cell death protein 1 (PD1) mRNA was analyzed. In a murine model, VitD3 was given intranasally in vivo and in vitro to lung cells with allergen and Rhinovirus. Results: In the cohorts of pre-school age children without (control) asthma, CRP and VitD3 levels inversely correlated. In preschool asthmatic children that did not receive VitD3 supplementation as infant had more episode of asthma exacerbation associated with high CRP serum level. In peripheral blood cells from control but not asthmatic children with higher serum levels of VitD3 had lower PD1 mRNA levels. In murine model, OVA intranasal challenge induced Innate Lymphoid Cells type 2 (ILC2)-associated markers and Eosinophils in BALF and VitD3 inhibited lung inflammation and ILC2 markers. Furthermore, VitD3 given intranasally, induced CD4+T cells and reduced PD1, T regulatory cells in the lung. Similarly, VitD3 had a suppressive role on CD4+PD1+ T cells involved in T cell exhaustion in the airways in the absence of ST2 after Rhinovirus infection. Conclusion: These data support an inhibitory role of VitD3 on T cell exhaustion after allergen and rhinovirus infection that is relevant for pediatric asthma.

scholarly journals Impact of multiple hits with cognate antigen on memory CD8+ T-cell fate

2020 ◽  
Vol 32 (9) ◽  
pp. 571-581 ◽  
Author(s):  
Shiki Takamura
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Memory T Cells ◽  
Cd8 T Cell ◽  
T Cell Subsets ◽  
Primary Immune Response ◽  
Memory T Cell ◽  
Cognate Antigen ◽  
Memory Cd8 T Cell

Abstract Antigen-driven activation of CD8+ T cells results in the development of a robust anti-pathogen response and ultimately leads to the establishment of long-lived memory T cells. During the primary response, CD8+ T cells interact multiple times with cognate antigen on distinct types of antigen-presenting cells. The timing, location and context of these antigen encounters significantly impact the differentiation programs initiated in the cells. Moderate re-activation in the periphery promotes the establishment of the tissue-resident memory T cells that serve as sentinels at the portal of pathogen entry. Under some circumstances, moderate re-activation of T cells in the periphery can result in the excessive expansion and accumulation of circulatory memory T cells, a process called memory inflation. In contrast, excessive re-activation stimuli generally impede conventional T-cell differentiation programs and can result in T-cell exhaustion. However, these conditions can also elicit a small population of exhausted T cells with a memory-like signature and self-renewal capability that are capable of responding to immunotherapy, and restoration of functional activity. Although it is clear that antigen re-encounter during the primary immune response has a significant impact on memory T-cell development, we still do not understand the molecular details that drive these fate decisions. Here, we review our understanding of how antigen encounters and re-activation events impact the array of memory CD8+ T-cell subsets subsequently generated. Identification of the molecular programs that drive memory T-cell generation will advance the development of new vaccine strategies that elicit high-quality CD8+ T-cell memory.

scholarly journals IL-6 Production by Dendritic Cells Is Dispensable for CD8+Memory T-Cell Generation

2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
Jean-François Daudelin ◽  
Mélissa Mathieu ◽  
Salix Boulet ◽  
Nathalie Labrecque
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
B Cell ◽  
Memory T Cells ◽  
T Cell Memory ◽  
Memory Cells ◽  
Differential Outcome ◽  
Memory T Cell ◽  
Antigen Presenting

Following activation, naïve CD8+T cells will differentiate into effectors that differ in their ability to survive: some will persist as memory cells while the majority will die by apoptosis. Signals given by antigen-presenting cells (APCs) at the time of priming modulate this differential outcome. We have recently shown that, in opposition to dendritic cell (DC), CD40-activated B-(CD40-B) cell vaccination fails to efficiently produce CD8+memory T cells. Understanding why CD40-B-cell vaccination does not lead to the generation of functional long-lived memory cells is essential to define the signals that should be provided to naïve T cells by APCs. Here we show that CD40-B cells produce very low amount of IL-6 when compared to DCs. However, supplementation with IL-6 during CD40-B-cell vaccination did not improve memory generation. Furthermore, IL-6-deficient DCs maintained the capacity to promote the formation of functional CD8+effectors and memory cells. Our results suggest that in APC vaccination models, IL-6 provided by the APCs is dispensable for proper CD8+T-cell memory generation.

scholarly journals Selective expression of IL-7 receptor on memory T cells identifies early CD40L-dependent generation of distinct CD8+ memory T cell subsets

2004 ◽  
Vol 101 (15) ◽  
pp. 5610-5615 ◽  
Author(s):  
K. M. Huster ◽  
V. Busch ◽  
M. Schiemann ◽  
K. Linkemann ◽  
K. M. Kerksiek ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Memory T Cells ◽  
T Cell Subsets ◽  
Memory T Cell ◽  
Selective Expression
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