scholarly journals T cell anergy in COVID-19 reflects virus persistence and poor outcomes

2020 ◽  
Author(s):  
Kerstin Renner ◽  
Christine Mueller ◽  
Charlotte Tiefenboeck ◽  
Jan-Niklas Salewski ◽  
Frederike Winter ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Severe Pneumonia ◽  
Cell Reactivity ◽  
Virus Persistence ◽  
T Cell Anergy ◽  
Cell Anergy ◽  
T Cell Reactivity ◽  
Poor Outcomes

Coronavirus disease 2019 (COVID-19) can lead to severe pneumonia and hyperinflammation. So far, insufficient or excessive T cell responses were described in patients. We applied novel approaches to analyze T cell reactivity and showed that T anergy is already present in non-ventilated COVID-19 patients, very pronounced in ventilated patients, strongly associated with virus persistence and reversible with clinical recovery. T cell activation was measured by downstream effects on responder cells like basophils, plasmacytoid dendritic cells, monocytes and neutrophils in whole blood and proved to be much more meaningful than classical readouts with PBMCs. Monocytes responded stronger in males than females and IL-2 partially reversed T cell anergy. Downstream markers of T cell anergy were also found in fresh blood samples of critically ill patients with severe T cell anergy. Based on our data we were able to develop a score to predict fatal outcomes and to identify patients that may benefit from strategies to overcome T cell anergy.

scholarly journals T cell anergy in COVID-19 reflects virus persistence and poor outcomes

2020 ◽  
Author(s):  
Kerstin Renner ◽  
Christine Müller ◽  
Charlotte Tiefenböck ◽  
Jan-Niklas Salewski ◽  
Frederike Winter ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Severe Pneumonia ◽  
Cell Reactivity ◽  
Virus Persistence ◽  
T Cell Anergy ◽  
Cell Anergy ◽  
T Cell Reactivity ◽  
Poor Outcomes

Abstract Coronavirus disease 2019 (COVID-19) can lead to severe pneumonia and hyperinflammation. So far, insufficient or excessive T cell responses were described in patients. We applied novel approaches to analyze T cell reactivity and showed that T anergy is already present in non-ventilated COVID-19 patients, very pronounced in ventilated patients, strongly associated with virus persistence and reversible with clinical recovery. T cell activation was measured by downstream effects on responder cells like basophils, plasmacytoid dendritic cells, monocytes and neutrophils in whole blood and proved to be much more meaningful than classical readouts with PBMCs. Monocytes responded stronger in males than females and IL-2 partially reversed T cell anergy. Downstream markers of T cell anergy were also found in fresh blood samples of critically ill patients with severe T cell anergy. Based on our data we were able to develop a score to predict fatal outcomes and to identify patients that may benefit from strategies to overcome T cell anergy.

scholarly journals Cyclo-oxygenase type 2-dependent prostaglandin E2 secretion is involved in retrovirus-induced T-cell dysfunction in mice

2004 ◽  
Vol 384 (3) ◽  
pp. 469-476 ◽  
Author(s):  
Souad RAHMOUNI ◽  
Einar Martin AANDAHL ◽  
Btissam NAYJIB ◽  
Mustapha ZEDDOU ◽  
Sandra GIANNINI ◽  
...  
Keyword(s):  
T Cell ◽  
Prostaglandin E2 ◽  
T Cell Activation ◽  
Cell Activation ◽  
Lymphoproliferative Disease ◽  
Cell Dysfunction ◽  
T Cell Anergy ◽  
T Cell Dysfunction ◽  
Cell Anergy

MAIDS (murine AIDS) is caused by infection with the murine leukaemia retrovirus RadLV-Rs and is characterized by a severe immunodeficiency and T-cell anergy combined with a lymphoproliferative disease affecting both B- and T-cells. Hyperactivation of the cAMP-protein kinase A pathway is involved in the T-cell dysfunction of MAIDS and HIV by inhibiting T-cell activation through the T-cell receptor. In the present study, we show that MAIDS involves a strong and selective up-regulation of cyclo-oxygenase type 2 in the CD11b+ subpopulation of T- and B-cells of the lymph nodes, leading to increased levels of PGE2 (prostaglandin E2). PGE2 activates the cAMP pathway through G-protein-coupled receptors. Treatment with cyclo-oxygenase type 2 inhibitors reduces the level of PGE2 and thereby reverses the T-cell anergy, restores the T-cell immune function and ameliorates the lymphoproliferative disease.

scholarly journals PAG-Associated FynT Regulates Calcium Signaling and Promotes Anergy in T Lymphocytes

2007 ◽  
Vol 27 (5) ◽  
pp. 1960-1973 ◽  
Author(s):  
Dominique Davidson ◽  
Burkhart Schraven ◽  
André Veillette
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tyrosine Phosphorylation ◽  
T Cell Activation ◽  
Protein Tyrosine Kinase ◽  
Cell Activation ◽  
T Cell Anergy ◽  
Cell Anergy ◽  
Anergic T Cells ◽  
Selective Enhancement

ABSTRACT Phosphoprotein associated with glycolipid-enriched membranes (PAG), also named Csk-binding protein (Cbp), is a transmembrane adaptor associated with lipid rafts. It is phosphorylated on multiple tyrosines located in the cytoplasmic domain. One tyrosine, tyrosine 314 (Y314) in the mouse, interacts with Csk, a protein tyrosine kinase that negatively regulates Src kinases. This interaction enables PAG to inhibit T-cell antigen receptor (TCR)-mediated T-cell activation. PAG also associates with the Src-related kinase FynT. Genetic studies indicated that FynT was required for PAG tyrosine phosphorylation and binding of PAG to Csk in T cells. Herein, we investigated the function and regulation of PAG-associated FynT. Our data showed that PAG was constitutively associated with FynT in unstimulated T cells and that this association was rapidly lost in response to TCR stimulation. Dissociation of the PAG-FynT complex preceded PAG dephosphorylation and PAG-Csk dissociation after TCR engagement. Interestingly, in anergic T cells, the association of PAG with FynT, but not Csk, was increased. Analyses of PAG mutants provided evidence that PAG interacted with FynT by way of tyrosines other than Y314. Enforced expression of a PAG variant interacting with FynT, but not Csk, caused a selective enhancement of TCR-triggered calcium fluxes in normal T cells. Furthermore, it promoted T-cell anergy. Both effects were absent in mice lacking FynT, implying that the effects were mediated by PAG-associated FynT. Hence, besides enabling PAG tyrosine phosphorylation and the PAG-Csk interaction, PAG-associated FynT can stimulate calcium signals and favor T-cell anergy. These data improve our comprehension of the function of PAG in T cells. They also further implicate FynT in T-cell anergy.

scholarly journals Immunodominant T-cell epitopes from the SARS-CoV-2 spike antigen reveal robust pre-existing T-cell immunity in unexposed individuals

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Swapnil Mahajan ◽  
Vasumathi Kode ◽  
Keshav Bhojak ◽  
Coral Karunakaran ◽  
Kayla Lee ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cd8 T Cell ◽  
T Cell Immunity ◽  
T Cell Epitopes ◽  
Cell Reactivity ◽  
Cell Immunity ◽  
T Cell Reactivity ◽  
Shared Epitopes

AbstractThe COVID-19 pandemic has revealed a range of disease phenotypes in infected patients with asymptomatic, mild, or severe clinical outcomes, but the mechanisms that determine such variable outcomes remain unresolved. In this study, we identified immunodominant CD8 T-cell epitopes in the spike antigen using a novel TCR-binding algorithm. The predicted epitopes induced robust T-cell activation in unexposed donors demonstrating pre-existing CD4 and CD8 T-cell immunity to SARS-CoV-2 antigen. The T-cell reactivity to the predicted epitopes was higher than the Spike-S1 and S2 peptide pools in the unexposed donors. A key finding of our study is that pre-existing T-cell immunity to SARS-CoV-2 is contributed by TCRs that recognize common viral antigens such as Influenza and CMV, even though the viral epitopes lack sequence identity to the SARS-CoV-2 epitopes. This finding is in contrast to multiple published studies in which pre-existing T-cell immunity is suggested to arise from shared epitopes between SARS-CoV-2 and other common cold-causing coronaviruses. However, our findings suggest that SARS-CoV-2 reactive T-cells are likely to be present in many individuals because of prior exposure to flu and CMV viruses.

scholarly journals The T-cell anergy induced by Leishmania amazonensis antigens is related with defective antigen presentation and apoptosis

2004 ◽  
Vol 76 (3) ◽  
pp. 519-527 ◽  
Author(s):  
Roberta O. Pinheiro ◽  
Eduardo F. Pinto ◽  
Alessandra B. Benedito ◽  
Ulisses G. Lopes ◽  
Bartira Rossi-Bergmann
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Antigen Presentation ◽  
T Cell Activation ◽  
Cell Activation ◽  
Leishmania Amazonensis ◽  
T Cell Anergy ◽  
Crude Antigen ◽  
Lymph Node Cells ◽  
Cell Anergy

Leishmania amazonensis is the main agent of diffuse cutaneous leishmaniasis, a disease associated with anergic immune responses. In this study we show that the crude antigen of Leishmania amazonensis (LaAg) but not L. braziliensis promastigotes (LbAg) contains substances that suppress mitogenic and spontaneous proliferative responses of T cells. The suppressive substances in LaAg are thermoresistant (100ºC/1h) and partially dependent on protease activity. T cell anergy was not due to a decreased production of growth factors as it was not reverted by addition of exogenous IL-2, IL-4, IFN-gamma or IL-12. LaAg did not inhibit anti-CD3-induced T cell activation, suggesting that anergy was due to a defect in antigen presentation. It was also not due to cell necrosis, but was accompanied by expressive DNA fragmentation in lymph node cells, indicative of apoptosis. Although pre-incubation of macrophages with LaAg prevented their capacity to present antigens, this effect was not due to apoptosis of the former. These results suggest that the T cell anergy found in diffuse leishmaniasis may be the result of parasite antigen-driven apoptosis of those cells following defective antigen presentation.

scholarly journals Thymic T cell anergy in autoimmune nonobese diabetic mice is mediated by deficient T cell receptor regulation of the pathway of p21ras activation.

1993 ◽  
Vol 177 (4) ◽  
pp. 1221-1226 ◽  
Author(s):  
M J Rapoport ◽  
A H Lazarus ◽  
A Jaramillo ◽  
E Speck ◽  
T L Delovitch
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tyrosine Phosphorylation ◽  
T Cell Receptor ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Receptor ◽  
T Cell Anergy ◽  
Nonobese Diabetic ◽  
Cell Anergy

Thymic T cell anergy, as manifested by thymocyte proliferative unresponsiveness to antigens expressed in the thymic environment, is commonly believed to mediate the acquisition of immunological self-tolerance. However, we previously found that thymic T cell anergy may lead to the breakdown of tolerance and predispose to autoimmunity in nonobese diabetic (NOD) mice. Here, we show that NOD thymic T cell anergy, as revealed by proliferative unresponsiveness in vitro after stimulation through the T cell receptor (TCR), is associated with defective TCR-mediated signal transduction along the PKC/p21ras/p42mapk pathway of T cell activation. PKC activity is reduced in NOD thymocytes. Activation of p21ras is deficient in quiescent and stimulated NOD T cells, and this is correlated with a significant reduction in the tyrosine phosphorylation of p42mapk, a serine/threonine kinase active downstream of p21ras. Treatment of NOD T cells with a phorbol ester not only enhances their p21ras activity and p42mapk tyrosine phosphorylation but also restores their proliferative responsiveness. Since p42mapk activity is required for progression through to S phase of the cell cycle, our data suggest that reduced tyrosine phosphorylation of p42mapk in stimulated NOD T cells may abrogate its activity and elicit the proliferative unresponsiveness of these cells.

scholarly journals Functional T Cell Reactivity to Melanocyte Antigens Is Lost during the Progression of Malignant Melanoma, but Is Restored by Immunization

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 223
Author(s):  
Anna Przybyla ◽  
Alexander A. Lehmann ◽  
Ting Zhang ◽  
Jacek Mackiewicz ◽  
Łukasz Galus ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Malignant Melanoma ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cd8 T Cell ◽  
Third Party ◽  
Healthy Human ◽  
Cell Reactivity ◽  
T Cell Reactivity

Healthy human subjects develop spontaneous CD8+ T cell responses to melanoma associated antigens (MA) expressed by normal melanocytes, such as Tyrosinase, MAGE-A3, Melan/Mart-1, gp100, and NY-ESO-1. This natural autoimmunity directed against melanocytes might confer protection against the development of malignant melanoma (MM), where MA are present as overexpressed tumor-associated antigens. Consistent with this notion we report here that functional T cell reactivity to MA was found to be significantly diminished to MAGE-A3, Melan-A/Mart-1, and gp100 in untreated MM patients. Three lines of evidence suggest that the MA-reactive T cells present in healthy subjects undergo exhaustion once MM establishes itself. First, only the MA-specific T cell reactivity was affected in the MM patients; that to third party recall antigens was not. Second, in these patients, the residual MA-specific T cells, unlike third party antigen reactive T cells, were functionally impaired, showing a diminished per cell IFN-γ productivity. Third, we show that immunization with MA restored natural CD8+ T cell autoimmunity to MA in 85% of the MM patients. The role of natural T cell autoimmunity to tumor-associated MA is discussed based on discrete levels of T cell activation thresholds.

Microglia induce myelin basic protein-specific T cell anergy or T cell activation, according to their state of activation

1999 ◽  
Vol 29 (10) ◽  
pp. 3063-3076 ◽  
Author(s):  
Malgosia K. Matyszak ◽  
Suzanne Denis-Donini ◽  
Stefania Citterio ◽  
Renato Longhi ◽  
Francesca Granucci ◽  
...  
Keyword(s):  
T Cell ◽  
Myelin Basic Protein ◽  
T Cell Activation ◽  
Cell Activation ◽  
Basic Protein ◽  
T Cell Anergy ◽  
Cell Anergy

scholarly journals IgE and T Cell Reactivity to a Comprehensive Panel of Cockroach Allergens in Relation to Disease

2021 ◽  
Vol 11 ◽  
Author(s):  
Anna Pomés ◽  
Véronique Schulten ◽  
Jill Glesner ◽  
Ricardo da Silva Antunes ◽  
Aaron Sutherland ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Specific Ige ◽  
Cell Reactivity ◽  
Ige Antibody ◽  
Recombinant Chitinase ◽  
Custom Made ◽  
T Cell Reactivity ◽  
Antibody Levels

IgE sensitization to cockroach allergens is associated with development of allergic diseases, such as asthma. To understand the relevance of different cockroach allergens for diagnosis and immunotherapy, a comprehensive analysis of IgE antibody levels and T cell reactivity to an expanded set of cockroach allergens and their relationship to disease was performed in a cohort of USA cockroach sensitized patients. IgE antibody levels to recombinant chitinase and hemocyanin were measured for 23 subjects by custom-made ImmunoCAPs and compared with IgE levels to eight cockroach allergens we previously reported for the same cohort. Ex vivo T cell activation (Ox40/PDL-1 expression) of PBMCs stimulated with peptide pools derived from 11 German cockroach proteins, including nine official cockroach allergens, plus chitinase and vitellogenin, was determined by flow cytometry. IgE prevalences to chitinase (17%) and hemocyanin (44%) were comparable to values for the other eight allergens that we previously reported (21–57%). Hemocyanin (Bla g 3), was a major allergen (one to which more than 50% of patients with an allergy to its source react) for a sub-group of 15 highly cockroach-sensitized subjects (IgE > 3.5 kUA/L: 53%). Chitinase was officially named as new allergen Bla g 12. Cockroach-specific IgE levels in plasma showed excellent correlation with the sum of 10 allergen-specific IgE (r = 0.94, p < 0.001). T cell reactivity to 11 proteins was highly variable among subjects, the highest being for vitellogenin, followed by Bla g 3. The main finding was that cockroach allergen-specific IgE and T cell reactivity patterns were unique per subject, and lacked immunodominant allergens and correlation with clinical phenotype/disease severity in the studied cohort. Knowing the subject-specific B/T cell reactivity profiles to a comprehensive panel of cockroach allergens will contribute to diagnosis of cockroach allergy and will be important for planning and assessing allergen immunotherapy outcomes, according to the allergen content in therapeutic cockroach extracts.

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