scholarly journals Long-lived virus-reactive memory T cells generated from purified cytokine-secreting T helper type 1 and type 2 effectors

2008 ◽  
Vol 205 (1) ◽  
pp. 53-61 ◽  
Author(s):  
Max Löhning ◽  
Ahmed N. Hegazy ◽  
Daniel D. Pinschewer ◽  
Dorothea Busse ◽  
Karl S. Lang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Cell ◽  
Memory T Cells ◽  
Effector T Cells ◽  
Memory Cells ◽  
T Helper ◽  
Cell Therapies ◽  
Memory T Cell

Many vaccination strategies and immune cell therapies aim at increasing the numbers of memory T cells reactive to protective antigens. However, the differentiation lineage and therefore the optimal generation conditions of CD4 memory cells remain controversial. Linear and divergent differentiation models have been proposed, suggesting CD4 memory T cell development from naive precursors either with or without an effector-stage intermediate, respectively. Here, we address this question by using newly available techniques for the identification and isolation of effector T cells secreting effector cytokines. In adoptive cell transfers into normal, nonlymphopenic mice, we show that long-lived virus-specific memory T cells can efficiently be generated from purified interferon γ–secreting T helper (Th) type 1 and interleukin (IL)-4– or IL-10–secreting Th2 effectors primed in vitro or in vivo. Importantly, such effector-derived memory T cells were functional in viral challenge infections. They proliferated vigorously, rapidly modulated IL-7 receptor expression, exhibited partial stability and flexibility of their cytokine patterns, and exerted differential effects on virus-induced immunopathology. Thus, cytokine-secreting effectors can evade activation-induced cell death and develop into long-lived functional memory cells. These findings demonstrate the efficiency of linear memory T cell differentiation and encourage the design of vaccines and immune cell therapies based on differentiated effector T cells.

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 The CD8+ memory T-cell state of readiness is actively maintained and reversible

Blood ◽  
2009 ◽  
Vol 114 (10) ◽  
pp. 2121-2130 ◽  
Author(s):  
Atef Allam ◽  
Dietrich B. Conze ◽  
Maria Letizia Giardino Torchia ◽  
Ivana Munitic ◽  
Hideo Yagita ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Function ◽  
Memory T Cells ◽  
Tumor Necrosis Factor Receptor ◽  
Dependent Manner ◽  
Memory Cells ◽  
Memory State ◽  
Memory T Cell

AbstractThe ability of the adaptive immune system to respond rapidly and robustly upon repeated antigen exposure is known as immunologic memory, and it is thought that acquisition of memory T-cell function is an irreversible differentiation event. In this study, we report that many phenotypic and functional characteristics of antigen-specific CD8 memory T cells are lost when they are deprived of contact with dendritic cells. Under these circumstances, memory T cells reverted from G1 to the G0 cell-cycle state and responded to stimulation like naive T cells, as assessed by proliferation, dependence upon costimulation, and interferon-γ production, without losing cell surface markers associated with memory. The memory state was maintained by signaling via members of the tumor necrosis factor receptor superfamily, CD27 and 4-1BB. Foxo1, a transcription factor involved in T-cell quiescence, was reduced in memory cells, and stimulation of naive CD8 cells via CD27 caused Foxo1 to be phosphorylated and emigrate from the nucleus in a phosphatidylinositol-3 kinase–dependent manner. Consistent with these results, maintenance of G1 in vivo was compromised in antigen-specific memory T cells in vesicular stomatitis virus-infected CD27-deficient mice. Therefore, sustaining the functional phenotype of T memory cells requires active signaling and maintenance.

scholarly journals Effect of Cyclophosphamide Treatment on Central and Effector Memory T Cells in Mice

2018 ◽  
Vol 37 (5) ◽  
pp. 373-382 ◽  
Author(s):  
Marcin Włodarczyk ◽  
Elżbieta Ograczyk ◽  
Magdalena Kowalewicz-Kulbat ◽  
Magdalena Druszczyńska ◽  
Wiesława Rudnicka ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Memory T Cells ◽  
Immunosuppressive Agent ◽  
Central Memory ◽  
Effector Memory ◽  
Memory Cells ◽  
Memory T Cell ◽  
Effector Memory T Cells ◽  
The Impact

Immunological memory is a key feature of adaptive immunity. It provides the organism with long-lived and robust protection against infection. The important question is whether cyclophosphamide (CP), as immunosuppressive agent used in cancer therapy and in some autoimmune diseases, may act on the memory T-cell population. We investigated the effect of CP on the percentage of central memory T cells (TCM) and effector memory T cells (TEM) in the mouse model of CP-induced immunosuppression (8-10-week-old male C57BL/6 mice CP treated for 7 days at the daily dose of 50 μg/g body weight [bw], manifested the best immunosuppression status, as compared to lower doses of CP: 10 or 20 μg/g bw). The CP induced a significant decrease in the percentage of CD8+ (TCM), compared to nonimmunosuppressed mice. This effect was not observed in the case of CD4+ TCM population. The percentage of gated TEM with CD4 and CD8 phenotype was significantly decreased in CP-treated mice, as compared to the control ones. Taken together, the above data indicate that CP-induced immunosuppression in mice leads to a reduction in the abundance of central memory cells possessing preferentially CD8+ phenotype as well as to a reduction in the percentage of effector memory cells (splenocytes both CD4+ and CD8+), compared to the cells from nonimmunosuppressed mice. These findings in mice described in this article may contribute to the understanding of the complexity of the immunological responses in humans and extend research on the impact of the CP model of immunosuppression in mice and memory T-cell populations.

scholarly journals PSGL-1 Is a T Cell Intrinsic Inhibitor That Regulates Effector and Memory Differentiation and Responses During Viral Infection

2021 ◽  
Vol 12 ◽  
Author(s):  
Roberto Tinoco ◽  
Emily N. Neubert ◽  
Christopher J. Stairiker ◽  
Monique L. Henriquez ◽  
Linda M. Bradley
Keyword(s):  
T Cells ◽  
T Cell ◽  
Viral Infection ◽  
Memory T Cells ◽  
Effector T Cells ◽  
T Cell Differentiation ◽  
Virus Infections ◽  
Effector T Cell ◽  
Memory T Cell ◽  
Cell Responses

Effective T cell differentiation during acute virus infections leads to the generation of effector T cells that mediate viral clearance, as well as memory T cells that confer protection against subsequent reinfection. While inhibitory immune checkpoints have been shown to promote T cell dysfunction during chronic virus infections and in tumors, their roles in fine tuning the differentiation and responses of effector and memory T cells are only just beginning to be appreciated. We previously identified PSGL-1 as a fundamental regulator of T cell exhaustion that sustains expression of several inhibitory receptors, including PD-1. We now show that PSGL-1 can restrict the magnitude of effector T cell responses and memory T cell development to acute LCMV virus infection by limiting survival, sustaining PD-1 expression, and reducing effector responses. After infection, PSGL-1-deficient effector T cells accumulated to a greater extent than wild type T cells, and preferentially generated memory precursor cells that displayed enhanced accumulation and functional capacity in response to TCR stimulation as persisting memory cells. Although, PSGL-1-deficient memory cells did not exhibit inherent greater sensitivity to cell death, they failed to respond to a homologous virus challenge after adoptive transfer into naïve hosts indicating an impaired capacity to generate memory effector T cell responses in the context of viral infection. These studies underscore the function of PSGL-1 as a key negative regulator of effector and memory T cell differentiation and suggest that PSGL-1 may limit excessive stimulation of memory T cells during acute viral infection.

scholarly journals CD8-positive memory T cells in tumor-draining lymph nodes of patients with breast cancer

2019 ◽  
Author(s):  
Yasmin Vahidi ◽  
Mandana Bagheri ◽  
Abbas Ghaderi ◽  
Zahra Faghih
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
T Cell ◽  
Lymph Nodes ◽  
Memory T Cells ◽  
T Cell Subsets ◽  
Axillary Lymph ◽  
Memory Cells ◽  
Memory T Cell ◽  
Draining Lymph Nodes

Abstract Background Human immunological memory is a hallmark of the adaptive immune system and plays an important role in the development of effective immune responses against tumors. In the present study, we aimed to determine the frequencies of CD8 + memory T cell subsets including stem memory T cells (TSCM) in tumor-draining lymph nodes of patients with breast cancer (BC).Methods Mononuclear cells were obtained from axillary lymph nodes of 52 untreated patients with BC and stained for CD8, CCR7, CD45RO, CD95 markers to detect different subtypes of memory cells in the CD8 + lymphocyte population. Data were acquired with four-color flow cytometry and analyzed with CellQuest Pro software.Results We observed that 47.65±2.66 of CD8+ lymphocytes expressed the CD45RO marker for memory T cells. Statistical analysis showed that the total frequency of central memory T cells (TCM) and their subset with low CD45RO expression was significantly higher in tumor-involved nodes compared to tumor-free ones (P=0.024 and P=0.017, respectively). Mean CD96 expression (based on mean fluorescence intensity) on the surface of TCM, their CD45RO hi TCM and CD45RO low subsets, and TSCM was higher in patients with stage II compared to those with stage I disease (P<0.05). The percentage of naive CD8 + T cells was significantly higher in tumor-involved lymph nodes compared to tumor-free ones (P=0.025).Conclusions Our data collectively indicate no significant differences in the frequencies of CD8 + lymphocytes or their memory T cell subsets in tumor-draining lymph nodes of patients with BC. However, the frequency of CD45 low TCM along with naive CD8 + lymphocytes was higher in tumor-involved nodes, which suggests that after long-term exposure to the antigen, and despite the immune reaction in order to provide a pool of effective memory cells, memory cell differentiation is blocked in early-stage (CD45RO low ) due to tumor-derived suppressive factors. Identifying the molecular and cellular mechanisms behind this suppression can provide invaluable tools for adoptive T cell therapies in cancer.

scholarly journals Antigen Delivered by Anthrax Lethal Toxin Induces the Development of Memory CD8+ T Cells That Can Be Rapidly Boosted and Display Effector Functions

2007 ◽  
Vol 76 (3) ◽  
pp. 1214-1222 ◽  
Author(s):  
Christine A. Shaw ◽  
Michael N. Starnbach
Keyword(s):  
T Cells ◽  
T Cell ◽  
Memory T Cells ◽  
Lethal Toxin ◽  
Host Cells ◽  
Effector Memory ◽  
Memory Cells ◽  
Anthrax Lethal Toxin ◽  
Memory T Cell ◽  
Presentation Pathway

ABSTRACT Memory CD8+ T cells are essential for protective immunity against many intracellular pathogens; therefore, stimulation of this population of cells is an important goal of vaccination. We have previously shown that a detoxified derivative of Bacillus anthracis anthrax lethal toxin (LT) can deliver heterologous CD8+ T-cell epitopes to the major histocompatibility complex class I processing and presentation pathway of murine host cells and that immunization of mice with these LT-antigen fusion proteins leads to the induction of antigen-specific CD8+ T cells. In this report we extend these findings to include a detailed characterization of the phenotypic and functional properties of the T cells stimulated by the LT-based system. We found that after an initial period of expansion and contraction, antigen-specific CD8+ T cells differentiated into a pool of memory cells that produced gamma interferon and displayed in vivo cytotoxic activity. The transition to memory cells appeared to be quite rapid based on an analysis of the phenotypic marker CD127 and the effectiveness of a booster immunization administered early after the initial immunization. We also investigated the composition of the memory T-cell pool induced by this system and found that while one immunization induced a mixture of effector memory T cells (CD62Llow) and central memory T cells (CD62Lhigh), a second immunization preferentially elevated the effector memory T-cell frequency. Finally, we demonstrated that mice that received prime-boost immunizations of LT-antigen proteins were more protected in a Listeria monocytogenes challenge model than mice that received only one immunization.

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 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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