scholarly journals Protection of bona fide T follicular memory cells during tissue isolation reveals their persistence, plasticity and functional impact

2019 ◽  
Author(s):  
Marco Künzli ◽  
David Schreiner ◽  
Tamara Pereboom ◽  
Nivedya Swarnalekha ◽  
Jonas Lötscher ◽  
...  
Keyword(s):  
Cell Death ◽  
Plasma Cells ◽  
Vaccine Development ◽  
Late Phase ◽  
Memory Cell ◽  
T Cell Subsets ◽  
List Type ◽  
Memory Cells ◽  
Elevated Expression ◽  
Metabolic Heterogeneity

SUMMARYCD4 memory T cells play an important role in protective immunity and are a key target in vaccine development. Many studies have focused on T central memory (TCM) cells, while the existence and functional significance of T follicular helper (TFH) memory cells is controversial. Here we show that TFH memory cells are highly susceptible to NAD induced cell death (NICD) during isolation from tissues, leading to their under-representation in prior studies. NICD blockade reveals the persistence of abundant TFH memory cells, with high expression of hallmark TFH markers, that persist to at least 400 days after infection, by which time TCM cells are no longer found. Using single cell RNA-seq we demonstrate that TFH memory cells are transcriptionally distinct from TCM cells, maintain stemness and self-renewal gene expression, and, in contrast to TCM cells, are multipotent following recall. Surprisingly, TFH memory cells concurrently express a distinct glycolytic signature similar to trained immune cells, including elevated expression of mTOR, HIF-1 and cAMP regulated genes. Late disruption of glycolysis/ICOS signaling leads to TFH memory cell depletion concomitant with decreased splenic plasma cells and circulating antibody titers, demonstrating both unique homeostatic regulation of memory TFH and their sustained function during the memory phase of the immune response. These results highlight the metabolic heterogeneity underlying distinct memory T cell subsets and establish TFH memory cells as an attractive target for the induction of long-lived adaptive immunity.HIGHLIGHTSCell death during isolation from the tissue prevents the full recovery of TFH memory cellsTFH memory cells are transcriptionally distinct from TCM cells and maintain a broader recall capacityTFH memory cells are maintained in the absence of antigen but require ICOS signaling and glycolysisTFH memory cells support late phase antibody production by splenic plasma cells

scholarly journals Long-lived T follicular helper cells retain plasticity and help sustain humoral immunity

2020 ◽  
Vol 5 (45) ◽  
pp. eaay5552 ◽  
Author(s):  
Marco Künzli ◽  
David Schreiner ◽  
Tamara C. Pereboom ◽  
Nivedya Swarnalekha ◽  
Ludivine C. Litzler ◽  
...  
Keyword(s):  
Plasma Cells ◽  
Vaccine Development ◽  
Folate Receptor ◽  
T Cell Subsets ◽  
Rna Seq ◽  
Follicular Helper ◽  
Elevated Expression ◽  
Antibody Titers ◽  
Memory Phase ◽  
Metabolic Heterogeneity

CD4+ memory T cells play an important role in protective immunity and are a key target in vaccine development. Many studies have focused on T central memory (Tcm) cells, whereas the existence and functional significance of long-lived T follicular helper (Tfh) cells are controversial. Here, we show that Tfh cells are highly susceptible to NAD-induced cell death (NICD) during isolation from tissues, leading to their underrepresentation in prior studies. NICD blockade reveals the persistence of abundant Tfh cells with high expression of hallmark Tfh markers to at least 400 days after infection, by which time Tcm cells are no longer found. Using single-cell RNA-seq, we demonstrate that long-lived Tfh cells are transcriptionally distinct from Tcm cells, maintain stemness and self-renewal gene expression, and, in contrast to Tcm cells, are multipotent after recall. At the protein level, we show that folate receptor 4 (FR4) robustly discriminates long-lived Tfh cells from Tcm cells. Unexpectedly, long-lived Tfh cells concurrently express a distinct glycolytic signature similar to trained immune cells, including elevated expression of mTOR-, HIF-1–, and cAMP-regulated genes. Late disruption of glycolysis/ICOS signaling leads to Tfh cell depletion concomitant with decreased splenic plasma cells and circulating antibody titers, demonstrating both unique homeostatic regulation of Tfh and their sustained function during the memory phase of the immune response. These results highlight the metabolic heterogeneity underlying distinct long-lived T cell subsets and establish Tfh cells as an attractive target for the induction of durable adaptive immunity.

696 Brentuximab vedotin, a CD30-directed antibody-drug conjugate, selectively depletes activated Tregs in vitro and in vivo

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A738-A738
Author(s):  
Bryan Grogan ◽  
Reice James ◽  
Michelle Ulrich ◽  
Shyra Gardai ◽  
Ryan Heiser ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Efflux Pump ◽  
Apoptotic Cell ◽  
T Cell Subsets ◽  
Memory Cells ◽  
Antibody Drug Conjugate ◽  
Selective Depletion

BackgroundRegulatory T cells (Tregs) play an important role in maintaining immune homeostasis, preventing excessive inflammation in normal tissues. In cancer, Tregs hamper anti-tumor immunosurveillance and facilitate immune evasion. Selective targeting of intratumoral Tregs is a potentially promising treatment approach. Orthogonal evaluation of tumor-infiltrating lymphocytes (TILs) in solid tumors in mice and humans have identified CCR8, and several tumor necrosis family receptors (TNFRs), including TNFSFR8 (CD30), as receptors differentially upregulated on intratumoral Tregs compared to normal tissue Tregs and other intratumoral T cells, making these intriguing therapeutic targets.Brentuximab vedotin (BV) is approved for classical Hodgkin lymphoma (cHL) across multiple lines of therapy including frontline use in stage III/IV cHL in combination with doxorubicin, vinblastine, and dacarbazine. BV is also approved for certain CD30-expressing T-cell lymphomas. BV is comprised of a CD30-directed monoclonal antibody conjugated to the highly potent microtubule-disrupting agent monomethyl auristatin E (MMAE).The activity of BV in lymphomas is thought to primarily result from tumor directed intracellular MMAE release, leading to mitotic arrest and apoptotic cell death.The role CD30 plays in normal immune function is unclear, with both costimulatory and proapoptotic roles described. CD30 is transiently upregulated following activation of memory T cells and expression has been linked to highly activated/suppressive IRF4+ effector Tregs.MethodsHere we evaluated the activity of BV on CD30-expressing T cell subsets in vitro and in vivo.ResultsTreatment of enriched T cell subsets with clinically relevant concentrations of BV drove selective depletion of CD30-expressing Tregs > CD30-expressingCD4+ T memory cells, with minimal effects on CD30-expressing CD8+ T memory cells. In a humanized xeno-GVHD model, treatment with BV selectively depleted Tregs resulting in accelerated wasting and robust T cell expansion. The observed differential activity on Tregs is likely attributable to significant increases in CD30 expression and reduced efflux pump activity relative to other T cell subsets. Interestingly, blockade of CD25 signaling prevents CD30 expression on T cell subsets without impacting proliferation, suggesting a link between CD25, the high affinity IL-2 receptor, and CD30 expression.ConclusionsTogether, these data suggest that BV may have an immunomodulatory effect through selective depletion of highly suppressive CD30-expressing Tregs.AcknowledgementsThe authors would like to thank Michael Harrison, PharmD for their assistance in abstract preparation.Ethics ApprovalAnimals studies were approved by and conducted in accordance with Seattle Genetics Institutional Care and Use Committee protocol #SGE-024.

scholarly journals Functional and genomic profiling of effector CD8 T cell subsets with distinct memory fates

2008 ◽  
Vol 205 (3) ◽  
pp. 625-640 ◽  
Author(s):  
Surojit Sarkar ◽  
Vandana Kalia ◽  
W. Nicholas Haining ◽  
Bogumila T. Konieczny ◽  
Shruti Subramaniam ◽  
...  
Keyword(s):  
T Cells ◽  
Expression Profiles ◽  
Acute Infection ◽  
Killer Cell ◽  
Gene Expression Profiles ◽  
Antigenic Stimulation ◽  
T Cell Subsets ◽  
Genomic Profiling ◽  
Memory Cells ◽  
Effector Cells

An important question in memory development is understanding the differences between effector CD8 T cells that die versus effector cells that survive and give rise to memory cells. In this study, we provide a comprehensive phenotypic, functional, and genomic profiling of terminal effectors and memory precursors. Using killer cell lectin-like receptor G1 as a marker to distinguish these effector subsets, we found that despite their diverse cell fates, both subsets possessed remarkably similar gene expression profiles and functioned as equally potent killer cells. However, only the memory precursors were capable of making interleukin (IL) 2, thus defining a novel effector cell that was cytotoxic, expressed granzyme B, and produced inflammatory cytokines in addition to IL-2. This effector population then differentiated into long-lived protective memory T cells capable of self-renewal and rapid recall responses. Experiments to understand the signals that regulate the generation of terminal effectors versus memory precursors showed that cells that continued to receive antigenic stimulation during the later stages of infection were more likely to become terminal effectors. Importantly, curtailing antigenic stimulation toward the tail end of the acute infection enhanced the generation of memory cells. These studies support the decreasing potential model of memory differentiation and show that the duration of antigenic stimulation is a critical regulator of memory formation.

The Combined Effects of Cycling Endurance and TID on Floating Gate Memory Cells

2021 ◽  
Author(s):  
Side Song ◽  
Guozhu Liu ◽  
Qi He ◽  
Xiang Gu ◽  
Genshen Hong ◽  
...  
Keyword(s):  
Radiation Effects ◽  
Memory Cell ◽  
Floating Gate ◽  
Combined Effects ◽  
Memory Cells ◽  
Threshold Voltage Shift ◽  
Floating Gate Memory ◽  
Interface Generation ◽  
Radiation Hardened ◽  
Radiation Induced

Abstract In this paper, the combined effects of cycling endurance and radiation on floating gate memory cell are investigated in detail, the results indicate that: 1.The programmed flash cells with a prior appropriate number of program and erase cycling stress exhibit much smaller threshold voltage shift than their counterpart in response to radiation, which is mainly ascribed to the recombination of trapped electrons (introduced by cycling stress) and trapped holes (introduced by irradiation) in the oxide surrounding the floating gate; 2.The radiation induced transconductance degradation in prior cycled flash cell is more severe than those without cycling stress in both of the programmed state and erased state; 3. Radiation is more likely to induce interface generation in programmed state than in erased state. This paper will be useful in understanding the issues involved in cycling endurance and radiation effects as well as in designing radiation hardened floating gate memory cells.

Analysis of Grain Boundary Dependent Memory Characteristics in Poly-Si One-Transistor Dynamic Random-Access Memory

2021 ◽  
Vol 21 (8) ◽  
pp. 4216-4222
Author(s):  
Songyi Yoo ◽  
In-Man Kang ◽  
Sung-Jae Cho ◽  
Wookyung Sun ◽  
Hyungsoon Shin
Keyword(s):  
Strong Electric Field ◽  
Memory Performance ◽  
Random Access ◽  
Memory Cell ◽  
Random Access Memory ◽  
Dynamic Random Access Memory ◽  
Thin Body ◽  
Memory Cells ◽  
Access Memory ◽  
Memory Characteristics

A capacitorless one-transistor dynamic random-access memory cell with a polysilicon body (poly-Si 1T-DRAM) has a cost-effective fabrication process and allows a three-dimensional stacked architecture that increases the integration density of memory cells. Also, since this device uses grain boundaries (GBs) as a storage region, it can be operated as a memory cell even in a thin body device. GBs are important to the memory characteristics of poly-Si 1T-DRAM because the amount of trapped charge in the GBs determines the memory’s data state. In this paper, we report on a statistical analysis of the memory characteristics of poly-Si 1T-DRAM cells according to the number and location of GBs using TCAD simulation. As the number of GBs increases, the sensing margin and retention time of memory cells deteriorate due to increasing trapped electron charge. Also, “0” state current increases and memory performance degrades in cells where all GBs are adjacent to the source or drain junction side in a strong electric field. These results mean that in poly-Si 1T-DRAM design, the number and location of GBs in a channel should be considered for optimal memory performance.

scholarly journals Differential ability of T cell subsets to undergo activation-induced cell death

1997 ◽  
Vol 94 (11) ◽  
pp. 5778-5783 ◽  
Author(s):  
A. S. Varadhachary ◽  
S. N. Perdow ◽  
C. Hu ◽  
M. Ramanarayanan ◽  
P. Salgame
Keyword(s):  
Cell Death ◽  
T Cell ◽  
T Cell Subsets ◽  
Activation Induced Cell Death ◽  
Differential Ability

scholarly journals Low-Dose Radiotherapy Has No Harmful Effects on Key Cells of Healthy Non-Inflamed Joints

2018 ◽  
Vol 19 (10) ◽  
pp. 3197 ◽  
Author(s):  
Lisa Deloch ◽  
Michael Rückert ◽  
Rainer Fietkau ◽  
Benjamin Frey ◽  
Udo Gaipl
Keyword(s):  
Bone Marrow ◽  
Cell Death ◽  
Low Dose ◽  
Immune Cell ◽  
Bone Marrow Cells ◽  
Positive Impact ◽  
Bone Destruction ◽  
T Cell Subsets ◽  
Low Dose Radiotherapy ◽  
Harmful Effects

Low-dose radiotherapy (LD-RT) for benign inflammatory and/or bone destructive diseases has been used long. Therefore, mechanistic investigations on cells being present in joints are mostly made in an inflammatory setting. This raises the question whether similar effects of LD-RT are also seen in healthy tissue and thus might cause possible harmful effects. We performed examinations on the functionality and phenotype of key cells within the joint, namely on fibroblast-like synoviocytes (FLS), osteoclasts and osteoblasts, as well as on immune cells. Low doses of ionizing radiation showed only a minor impact on cytokine release by healthy FLS as well as on molecules involved in cartilage and bone destruction and had no significant impact on cell death and migration properties. The bone resorbing abilities of healthy osteoclasts was slightly reduced following LD-RT and a positive impact on bone formation of healthy osteoblasts was observed after in particular exposure to 0.5 Gray (Gy). Cell death rates of bone-marrow cells were only marginally increased and immune cell composition of the bone marrow showed a slight shift from CD8+ to CD4+ T cell subsets. Taken together, our results indicate that LD-RT with particularly a single dose of 0.5 Gy has no harmful effects on cells of healthy joints.

scholarly journals Eimeria falciformisBayerHaberkorn1970 and novel wild derived isolates from house mice: differences in parasite lifecycle, pathogenicity and host immune reactions

2019 ◽  
Author(s):  
E. Al-khlifeh ◽  
A. Balard ◽  
V.H. Jarquín-Díaz ◽  
A. Weyrich ◽  
G. Wibbelt ◽  
...  
Keyword(s):  
Weight Loss ◽  
Plasma Cells ◽  
Immune Cell ◽  
Laboratory Strain ◽  
Cytokine Gene Expression ◽  
House Mice ◽  
Evolutionary Divergence ◽  
List Type ◽  
Immune Reactions ◽  
Natural Systems

AbstractSpecies ofEimeria(Apicomplexa:Coccidia) differ in the timing of lifecycle progression and resulting infections vary in host immune reactions and pathology they induce.Eimeriainfections in house mice are used as models for basic immunology and the most commonly used isolates have been passaged in laboratory mice for over 50 years. We questioned in how far such isolates are still representative for infections in natural systems.In the current study, we address this question by comparing the “laboratory isolate”E. falciformisBayerHaberkorn1970 with a novel, wild derived isolateE. falciformisBrandenburg88, and contrast this with another novel wild derived isolate,E. ferrisiBrandenburg64. We compare parasite lifecycle progression. We relate this to immune cell infiltration at the site of infection (in the caecum) and cytokine gene expression in the spleen as a measure of host immune response. We assess host weight loss as a measure of pathogenicity.A species-specific slower parasite lifecyle progression and higher pathogenicity are observed forE. falciformis vs. E. ferrisi.Host cytokines, in contrast, are expressed at significantly higher level in the spleen of mice infected with theE. falciformislaboratory isolate than in both wild derived isolates, irrespective of the species. Differences in histopathology are observable between all three isolates: TheE. falciformisBayerHaberkorn1970 laboratory isolate induces the strongest inflammation and cellular infiltration (with lymphocytes, plasma cells and eosinophilic granulocytes) followed by the wild derivedE. falciformisBrandenburg88 isolate.E. ferrisiBrandenburg64 is inducing milder histological changes than bothE. falciformisisolates.It can be speculated that the serial passaging ofE. falciformisBayerHaberkorn1970 has resulted in evolutionary divergence rendering this isolate more virulent in NMRI mice. Caution is needed when findings from experimental infection with laboratory strains should be integrated with observations in natural systems.HighlightsE. ferrisihas a shorter pre-patency thanwild-derived and laboratory isolates ofE. falciformis.E. ferrisiis less virulent than bothE. falciformisisolates and the timing of maximal oocyst shedding relative to host weight loss differs.The laboratory strain ofE. falciformisinduces stronger cytokine expression in the spleen than both wild derived strains ofE. falciformisandE. ferrisi.The laboratory strain ofE. falciformisinduces stronger tissue infiltration of immune cells than the wild-derived strain.E. ferrisiinfections are associated with the lowest infiltration.

scholarly journals The human liver microenvironment shapes the homing and function of CD4+T-cell populations

2020 ◽  
Author(s):  
Benjamin G. Wiggins ◽  
Laura J. Pallett ◽  
Xiaoyan Li ◽  
Scott P. Davies ◽  
Oliver E. Amin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Human Liver ◽  
Memory T Cells ◽  
T Cell Subsets ◽  
Cell Phenotype ◽  
List Type ◽  
Cd69 Expression ◽  
Resident Memory T Cells

ABSTRACTBackground & AimsTissue-resident memory T cells (TRM) are important immune sentinels that provide efficient in situ immunity. Liver-resident CD8+ TRM have been previously described, and contribute to viral control in persistent hepatotropic infections. However, little is known regarding liver CD4+ TRM cells. Here we profiled resident and non-resident intrahepatic CD4+ T cell subsets, assessing their phenotype, function, differential generation requirements and roles in hepatotropic infection.MethodsLiver tissue was obtained from 173 subjects with (n=109) or without (n=64) hepatic pathology. Multiparametric flow cytometry and immunofluorescence imaging examined T cell phenotype, functionality and location. Liver T cell function was determined after stimulation with anti-CD3/CD28 and PMA/Ionomycin. Co-cultures of blood-derived lymphocytes with hepatocyte cell lines, primary biliary epithelial cells, and precision-cut autologous liver slices were used to investigate the acquisition of liver-resident phenotypes.ResultsCD69 expression delineated two distinct subsets in the human liver. CD69HI cells were identified as CD4+ TRM due to exclusion from the circulation, a residency-associated phenotype (CXCR6+CD49a+S1PR1-PD-1+), restriction to specific liver niches, and ability to produce robust type-1 multifunctional cytokine responses. Conversely, CD69INT were an activated T cell population also found in the peripheral circulation, with a distinct homing profile (CX3CR1+CXCR3+CXCR1+), and a bias towards IL-4 production. Frequencies of CD69INT cells correlated with the degree of fibrosis in chronic hepatitis B virus infection. Interaction with hepatic epithelia was sufficient to generate CD69INT cells, while additional signals from the liver microenvironment were required to generate liver-resident CD69HI cells.ConclusionsIntermediate and high CD69 expression demarcates two discrete intrahepatic CD4+ T cell subsets with distinct developmental and functional profiles.Graphical AbstractHighlightsCD69HI (CXCR6+CD49a+S1PR1-PD-1+) are the CD4+ TRM of the human liverHepatic CD69INTCD4+ T-cells are distinct, activated, and recirculation-competentStimulation evokes respective IFN-γ and IL-4 responses in CD69HI and CD69INT cellsCD69INT cell frequencies correlate with worsening fibrosis in chronic HBV patientsLiver slice cultures allow differentiation of CD69INT and CD69HI cells from bloodLay summaryTissue-resident memory T cells (TRM) orchestrate regional immune responses, but much of the biology of liver-resident CD4+ TRM remains unknown. We found high expression of cell-surface protein CD69 defined hepatic CD4+ TRM, while simultaneously uncovering a distinct novel recirculatory CD69INT CD4+ T cell subset. Both subsets displayed unique immune receptor profiles, were functionally skewed towards type-1 and type-2 responses respectively, and had distinct generation requirements, highlighting the potential for differential roles in the immunopathology of chronic liver diseases.

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