scholarly journals Uremia-Associated Immunological Aging and Severity of COVID-19 Infection

2021 ◽  
Vol 8 ◽  
Author(s):  
Michiel G. H. Betjes
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Lung Parenchyma ◽  
Effector T Cells ◽  
High Morbidity ◽  
Memory T Cell ◽  
Co Morbidity ◽  
Complicated Course ◽  
One Year ◽  
Morbid Conditions

One year after the start of the COVID-19 pandemic it has become clear that some groups of individuals are at particular high risk of a complicated course of infection resulting in high morbidity and mortality. Two specific risk factors are most prominent, old age and the presence of co-morbidity. Recent studies have shown that patients with compromised renal function, especially those treated with renal replacement therapy or having received a kidney transplant are at a much higher risk for severe COVID infection and increased mortality. This may be in part due to the increased prevalence of co-morbid conditions in these patients but specific alterations in their immune system, reflecting premature immunological aging, may be equally important. In this review the different aspects, in particular thymus function and memory T cell expansion, of uremia-associated immunological aging are reviewed with respect to COVID 19 infection. In essence, the decreased generation of naïve T cells may be instrumental in suboptimal anti-viral immune responses while the relatively uncontrolled expansion of effector T cells may facilitate the feared phase of the COVID-19 infection with excessive and live-threatening inflammation of the lung parenchyma.

scholarly journals Allergic pulmonary inflammation in mice is dependent on eosinophil-induced recruitment of effector T cells

2008 ◽  
Vol 205 (3) ◽  
pp. 699-710 ◽  
Author(s):  
Elizabeth A. Jacobsen ◽  
Sergei I. Ochkur ◽  
Ralph S. Pero ◽  
Anna G. Taranova ◽  
Cheryl A. Protheroe ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Alternative Hypothesis ◽  
Pulmonary Inflammation ◽  
Allergen Challenge ◽  
Effector T Cells ◽  
Th2 Cytokines ◽  
Cell Responses ◽  
Th2 Chemokines

The current paradigm surrounding allergen-mediated T helper type 2 (Th2) immune responses in the lung suggests an almost hegemonic role for T cells. Our studies propose an alternative hypothesis implicating eosinophils in the regulation of pulmonary T cell responses. In particular, ovalbumin (OVA)-sensitized/challenged mice devoid of eosinophils (the transgenic line PHIL) have reduced airway levels of Th2 cytokines relative to the OVA-treated wild type that correlated with a reduced ability to recruit effector T cells to the lung. Adoptive transfer of Th2-polarized OVA-specific transgenic T cells (OT-II) alone into OVA-challenged PHIL recipient mice failed to restore Th2 cytokines, airway histopathologies, and, most importantly, the recruitment of pulmonary effector T cells. In contrast, the combined transfer of OT-II cells and eosinophils into PHIL mice resulted in the accumulation of effector T cells and a concomitant increase in both airway Th2 immune responses and histopathologies. Moreover, we show that eosinophils elicit the expression of the Th2 chemokines thymus- and activation-regulated chemokine/CCL17 and macrophage-derived chemokine/CCL22 in the lung after allergen challenge, and blockade of these chemokines inhibited the recruitment of effector T cells. In summary, the data suggest that pulmonary eosinophils are required for the localized recruitment of effector T cells.

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 MCMV-based vaccine vectors expressing full-length viral proteins provide long-term humoral immune protection upon a single-shot vaccination

2022 ◽  
Author(s):  
Yeonsu Kim ◽  
Xiaoyan Zheng ◽  
Kathrin Eschke ◽  
M. Zeeshan Chaudhry ◽  
Federico Bertoglio ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Influenza A ◽  
High Morbidity ◽  
Single Shot ◽  
Respiratory Pathogens ◽  
Antigenic Peptides ◽  
Immune Protection ◽  
Vaccine Vectors

AbstractGlobal pandemics caused by influenza or coronaviruses cause severe disruptions to public health and lead to high morbidity and mortality. There remains a medical need for vaccines against these pathogens. CMV (cytomegalovirus) is a β-herpesvirus that induces uniquely robust immune responses in which remarkably large populations of antigen-specific CD8+ T cells are maintained for a lifetime. Hence, CMV has been proposed and investigated as a novel vaccine vector for expressing antigenic peptides or proteins to elicit protective cellular immune responses against numerous pathogens. We generated two recombinant murine CMV (MCMV) vaccine vectors expressing hemagglutinin (HA) of influenza A virus (MCMVHA) or the spike protein of severe acute respiratory syndrome coronavirus 2 (MCMVS). A single injection of MCMVs expressing either viral protein induced potent neutralizing antibody responses, which strengthened over time. Importantly, MCMVHA-vaccinated mice were protected from illness following challenge with the influenza virus, and we excluded that this protection was due to the effects of memory T cells. Conclusively, we show here that MCMV vectors induce not only long-term cellular immunity but also humoral responses that provide long-term immune protection against clinically relevant respiratory pathogens.

A Prophylactic Protocol for the Prevention of Inhibitor Formation in Gene Therapy for Hemophilia B by Shifting the Balance from An Effector to a Regulatory T Cell Response

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3531-3531
Author(s):  
Sushrusha Nayak ◽  
Brad Hoffman ◽  
Mario Cooper ◽  
Mark Atkinson ◽  
Ou Cao ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Gene Transfer ◽  
Immune Responses ◽  
Substantial Reduction ◽  
Effector T Cells ◽  
T Cell Response ◽  
Hemophilia B ◽  
Specific Tolerance ◽  
Specific Peptide

Abstract Gene and protein treatments for severe hemophilia have been limited by immune responses to the therapeutic protein. Prophylactic protocols for the prevention of immune responses may be key to successful therapy. Our previous work has demonstrated the importance of regulatory T cells (Treg) in immune tolerance to therapeutic gene products. We attempted to induce antigen-specific tolerance to F.IX in AAV1-mediated muscle gene transfer with a novel protocol utilizing a combination of the immune suppressive drug Rapamycin (rapa), IL-10 cytokine, and an antigen specific CD4+ T cell epitope. Treg deficient (DO.11.10-tg Rag2−/−) BALB/c mice transgenic for ovalbumin -specific T cell receptor were used to determine the mechanism of tolerance. Groups of mice (n=4) were injected (IP) with rapa/IL-10/ova or Rapa/IL-10/irrelavent peptide (control) 3 times per week for 1, 3, or 4 weeks. Rapa/IL-10/ova treatment resulted in significant deletion of CD4+ cells from >30% of total splenic lymphocytes to 6% by 4 weeks. Apoptosis increased from 6% to 18% of CD4+ T cells over the duration of treatment. Apoptotic cells expressed FasL, showed an increase in activation marker CD69 and a decrease in CD62L, indicating Activation Induced Cell Death. Concomitant with the deletion of effector T cells, an increase in CD4+CD25+FoxP3+ ova-specific T cells was observed. Comparative studies after 3 weeks of treatment showed that the percentage of CD4+CD25+FoxP3+ ova-specific T cells in the peripheral blood, spleen, lymph nodes, and thymus averaged 28%, 19%, 22% and 2.4% in the rapa/IL-10/ova treated animals as opposed to 0.9%, 0.4%, 0% and 0.02% in the Rapa/IL-10/irrelavent peptide controls, respectively. In vitro suppression assay depicted absence of proliferation of effector T cells in presence of CD4+CD25+FoxP3+ isolated after 3 weeks of treatment. Flow cytometric analyses showed that the rate of apoptosis was higher in Teff compared to Treg, indicating a greater resistance of Treg to inhibition by rapamycin. Next, we tested this protocol for prevention of inhibitor formation in hemophilia B. Factor IX knockout mice (C3H/HeJ F9−/−) were injected IM with a dose of 1×10^11 vg AAV1-CMV-hFIX during the third week of treatment with rap/IL-10/hF.IX-specific peptide or Rap/IL-10/irrelavent peptide (control) in a 4-week treatment protocol. Substantial reduction in the inhibitor titers was observed after 2 months (<2 BU, representing the background of our assay) in the specific peptide protocol as compared to the irrelevant peptide controls (4–5 BU) and gene transfer only controls (4–19 BU). Clotting times (aPTT) were reduced to 45–53 seconds in the rap/IL-10/specific-peptide treated animals compared to 61– 86 seconds in the rap/IL-10/irrelavent peptide controls and 64–89 seconds in the non-immune suppressed controls. Animals treated with the hF.IX-specific tolerance protocol remained inhibitor-free for >5 months. In these immune competent animals, rapamycin administration caused a transient decline in T and B lymphocyte numbers and neutrophilia, which resolved between 5 and 7 months. In summary, our results demonstrate that the proposed prophylactic protocol can be successful in preventing immune responses to F.IX and may also be applicable to treatment of other inherited protein deficiencies.

CXCR3 Is Required for the Efficient Recruitment of Bone Marrow-Resident Memory T Cells to Inflamed Tissues,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3242-3242
Author(s):  
Robbert van der Voort ◽  
Claudia Brandao ◽  
Thomas J. Volman ◽  
Viviènne Verweij ◽  
Klaas van Gisbergen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Cd8 T Cells ◽  
Memory T Cells ◽  
Central Memory ◽  
T Cell Subsets ◽  
Effector Memory ◽  
Memory T Cell

Abstract Abstract 3242 Although the importance of the bone marrow (BM) in hematopoiesis is well known, its function in adaptive immune responses has only recently been acknowledged. Currently it is known that the BM contains fully functional CD4+ and CD8+ T cells that can engage in both primary and secondary immune responses. Interestingly, most of these T cells belong to the memory T cell lineage, identifying the BM as one of the largest memory T cell reservoirs in the body. Since not much is known about the trafficking of BM T cells, we compared the homing phenotype and function of T cell subsets in the BM, blood, spleen and peripheral lymph nodes (pLN). In addition, we determined the expression of chemokine mRNA and protein levels in the BM and other lymphoid organs. We confirmed that at least 80% of the CD4+ and 60% of the CD8+ BM T cells have a memory phenotype, and that most CD4+ T cells belong to the effector memory lineage, while the CD8+ population predominantly consists of central memory T cells. Most BM T cells expressed the chemokine receptor CXCR3, the adhesion molecules P-selectin glycoprotein ligand 1 and VLA-4, and increased levels of CD44 and LFA-1, as compared to T cells from the spleen. In addition, L-selectin was absent from most CD4+ BM T cells, but present on virtually all CD8+ T cells. Notably, the percentage of CXCR3+ T cells within the effector memory and central memory subsets from BM was higher than within the same subsets from pLN. Furthermore, BM contained significant mRNA levels of the CXCR3 ligands CXCL9, CXCL10 and CXCL11. An in vivo migration assay using a mixture of fluorescent-labeled T cells from CXCR3-deficient mice and control mice indicated however that during homeostasis CXCR3 does not play a major role in BM entry or retention. These data suggest that CXCR3 expressed by memory T cells is rather involved in BM exit, than in BM entry. Indeed, we observed that, as compared to control mice, CXCR3−/− mice contained significantly more CD4+ and CD8+ T cells in their BM. Additional in vitro assays demonstrated that CD4+ and CD8+ BM T cells migrated vigorously in response to CXCL9 and CXCL10, generally released in high concentrations during inflammation. Finally, we demonstrate that CXCR3−/− effector/effector memory T cells, but not wild type T cells, accumulate in the BM of mice infected with lymphocytic choriomeningitis virus. Altogether, these data demonstrate that the BM is a major reservoir of memory T cells that employ CXCR3 to quickly respond to chemotactic signals from inflamed tissues. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Competition for IL-2 between Regulatory and Effector T Cells to Chisel Immune Responses

2012 ◽  
Vol 3 ◽  
Author(s):  
Thomas Höfer ◽  
Oleg Krichevsky ◽  
Grégoire Altan-Bonnet
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Effector T Cells

scholarly journals Regulatory T Cells Inhibit T Cell Activity by Downregulating CD137 Ligand via CD137 Trogocytosis

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 353
Author(s):  
Khang Luu ◽  
Mugdha Vijay Patwardhan ◽  
Qun Zeng ◽  
Stina L. Wickström ◽  
Andreas Lundqvist ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Immune Responses ◽  
Costimulatory Molecule ◽  
Cell Activity ◽  
Effector T Cells ◽  
Comparable Data ◽  
Activated T Cells ◽  
Evolutionarily Conserved ◽  
Antigen Presenting

CD137 is a costimulatory molecule expressed on activated T cells. CD137 ligand (CD137L) is expressed by antigen presenting cells (APC), which use the CD137—CD137L system to enhance immune responses. It was, therefore, surprising to discover CD137 expression on regulatory T cells (Treg). The function of CD137 in Treg are controversial. While some studies report that CD137 signalling converts Treg to effector T cells (Teff), other studies find that CD137-expressing Treg display a stronger inhibitory activity than CD137- Treg. Here, we describe that CD137 on Treg binds to CD137L on APC, upon which one of the two molecules is transferred via trogocytosis to the other cell, where CD137—CD137L forms a complex that is internalized and deprives APC of the immune-stimulatory CD137L. Truncated forms of CD137 that lack the cytoplasmic domain of CD137 are also able to downregulate CD137L, demonstrating that CD137 signalling is not required. Comparable data have been obtained with human and murine cells, indicating that this mechanism is evolutionarily conserved. These data describe trogocytosis of CD137 and CD137L as a new mechanism employed by Treg to control immune responses by downregulating the immunostimulatory CD137L on APC.

scholarly journals Egr2 and 3 control adaptive immune responses by temporally uncoupling expansion from T cell differentiation

2017 ◽  
Vol 214 (6) ◽  
pp. 1787-1808 ◽  
Author(s):  
Tizong Miao ◽  
Alistair L.J. Symonds ◽  
Randeep Singh ◽  
Janine D. Symonds ◽  
Ane Ogbe ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Clonal Expansion ◽  
Effector T Cells ◽  
T Cell Differentiation ◽  
Fundamental Function ◽  
Adaptive Immune ◽  
Expression Of Genes ◽  
Proliferation And Differentiation ◽  
Upstream Regulators

Egr2 and 3 are important for maintaining immune homeostasis. Here we define a fundamental function of Egr2 and 3 operating as a checkpoint that controls the transition between clonal expansion and differentiation of effector T cells. Egr2 and 3 deficiency resulted in defective clonal expansion but hyperactivation and excessive differentiation of T cells in response to viral infection. Conversely, sustained Egr2 expression enhanced expansion but severely impaired effector differentiation. Egr2 bound to and controlled the expression of genes regulating proliferation (Myc and Myb) and differentiation repressors (Bcl6, Id3), while repressing transcription factors required for effector function (Zeb2, RORa, RORc, and Bhlhe40). Egr2 and 3 expression in T cells was regulated reciprocally by antigen and IFNγ, providing a mechanism for adjusting proliferation and differentiation of individual T cells. Thus, Egr2 and 3 are upstream regulators of effector CD4 and CD8 T cells that are essential for optimal responses with limited immunopathology.

Hybrid spherical nucleotide nanoparticles can enhance the synergistic anti-tumor effect of CTLA-4 and PD-1 blockades

2020 ◽  
Vol 8 (17) ◽  
pp. 4757-4766
Author(s):  
Jing Zhang ◽  
Dan Liu ◽  
Jiale Liu ◽  
Yanfeng Han ◽  
Haiyan Xu ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Effector T Cells ◽  
Suppressive Function

hSNPs elicit robust anti-tumor immune responses through targeted evading the immune suppressive function of Tregs and TIM3+ exhausted-like CD8+ T cells while promoting CD4+ T cells, especially ICOS+ Th1-like CD4+ T cells, and CD8+ effector T cells in a nonredundant fashion.

scholarly journals FXR mediates T cell-intrinsic responses to reduced feeding during infection

2020 ◽  
Vol 117 (52) ◽  
pp. 33446-33454
Author(s):  
Clarissa Campbell ◽  
Francois Marchildon ◽  
Anthony J. Michaels ◽  
Naofumi Takemoto ◽  
Joris van der Veeken ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Cell Survival ◽  
Sickness Behavior ◽  
Effector T Cells ◽  
Farnesoid X Receptor ◽  
Limiting Nutrient ◽  
Cognate Antigen

Reduced nutrient intake is a widely conserved manifestation of sickness behavior with poorly characterized effects on adaptive immune responses. During infectious challenges, naive T cells encountering their cognate antigen become activated and differentiate into highly proliferative effector T cells. Despite their evident metabolic shift upon activation, it remains unclear how effector T cells respond to changes in nutrient availability in vivo. Here, we show that spontaneous or imposed feeding reduction during infection decreases the numbers of splenic lymphocytes. Effector T cells showed cell-intrinsic responses dependent on the nuclear receptor Farnesoid X Receptor (FXR). Deletion of FXR in T cells prevented starvation-induced loss of lymphocytes and increased effector T cell fitness in nutrient-limiting conditions, but imparted greater weight loss to the host. FXR deficiency increased the contribution of glutamine and fatty acids toward respiration and enhanced cell survival under low-glucose conditions. Provision of glucose during anorexia of infection rescued effector T cells, suggesting that this sugar is a limiting nutrient for activated lymphocytes and that alternative fuel usage may affect cell survival in starved animals. Altogether, we identified a mechanism by which the host scales immune responses according to food intake, featuring FXR as a T cell-intrinsic sensor.

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