scholarly journals Impaired Cytotoxic CD8+ T Cell Response in Elderly COVID-19 Patients

mBio ◽  
2020 ◽  
Vol 11 (5) ◽  
Author(s):  
Jaana Westmeier ◽  
Krystallenia Paniskaki ◽  
Zehra Karaköse ◽  
Tanja Werner ◽  
Kathrin Sutter ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Elderly Patients ◽  
Cell Response ◽  
Acute Infection ◽  
T Cell Response ◽  
T Cell Subsets ◽  
Cytotoxic T Cell ◽  
Cytotoxic Response ◽  
Cytotoxic Molecules

ABSTRACT Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection induces a T cell response that most likely contributes to virus control in COVID-19 patients but may also induce immunopathology. Until now, the cytotoxic T cell response has not been very well characterized in COVID-19 patients. Here, we analyzed the differentiation and cytotoxic profile of T cells in 30 cases of mild COVID-19 during acute infection. SARS-CoV-2 infection induced a cytotoxic response of CD8+ T cells, but not CD4+ T cells, characterized by the simultaneous production of granzyme A and B as well as perforin within different effector CD8+ T cell subsets. PD-1-expressing CD8+ T cells also produced cytotoxic molecules during acute infection, indicating that they were not functionally exhausted. However, in COVID-19 patients over the age of 80 years, the cytotoxic T cell potential was diminished, especially in effector memory and terminally differentiated effector CD8+ cells, showing that elderly patients have impaired cellular immunity against SARS-CoV-2. Our data provide valuable information about T cell responses in COVID-19 patients that may also have important implications for vaccine development. IMPORTANCE Cytotoxic T cells are responsible for the elimination of infected cells and are key players in the control of viruses. CD8+ T cells with an effector phenotype express cytotoxic molecules and are able to perform target cell killing. COVID-19 patients with a mild disease course were analyzed for the differentiation status and cytotoxic profile of CD8+ T cells. SARS-CoV-2 infection induced a vigorous cytotoxic CD8+ T cell response. However, this cytotoxic profile of T cells was not detected in COVID-19 patients over the age of 80 years. Thus, the absence of a cytotoxic response in elderly patients might be a possible reason for the more frequent severity of COVID-19 in this age group than in younger patients.

scholarly journals Impaired cytotoxic CD8+ T cell response in elderly COVID-19 patients

2020 ◽  
Author(s):  
Jaana Westmeier ◽  
Krystallenia Paniskaki ◽  
Zehra Karaköse ◽  
Tanja Werner ◽  
Kathrin Sutter ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Elderly Patients ◽  
Cd8 T Cells ◽  
Cell Response ◽  
Acute Infection ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Cytotoxic T Cell ◽  
Cytotoxic Molecules

AbstractSARS-CoV-2 infection induces a T cell response that most likely contributes to virus control in COVID-19 patients, but may also induce immunopathology. Until now, the cytotoxic T cell response has not been very well characterized in COVID-19 patients.Here, we analyzed the differentiation and cytotoxic profile of T cells in 30 cases of mild COVID-19 during acute infection. SARS-CoV-2 infection induced a cytotoxic response of CD8+ T cells, but not CD4+ T cells, characterized by the simultaneous production of granzyme A and B, as well as perforin within different effector CD8+ T cell subsets. PD-1 expressing CD8+ T cells also produced cytotoxic molecules during acute infection indicating that they were not functionally exhausted. However, in COVID-19 patients over the age of 80 years the cytotoxic T cell potential was diminished, especially in effector memory and terminally differentiated effector CD8+ cells, showing that elderly patients have impaired cellular immunity against SARS-CoV-2.Our data provides valuable information about T cell responses in COVID-19 patients that may also have important implications for vaccine development.ImportanceCytotoxic T cells are responsible for the elimination of infected cells and are key players for the control of viruses. CD8+ T cells with an effector phenotype express cytotoxic molecules and are able to perform target cell killing. COVID-19 patients with a mild disease course were analyzed for the differentiation status and cytotoxic profile of CD8+ T cells. SARS-CoV-2 infection induced a vigorous cytotoxic CD8+ T cell response. However, this cytotoxic profile of T cells was not detected in COVID-19 patients over the age of 80 years. Thus, the absence of a cytotoxic response in elderly patients might be a possible reason for the more frequent severity of COVID-19 in this age group in comparison to younger patients.

scholarly journals Effects of an Epitope-Specific CD8+ T-Cell Response on Murine Coronavirus Central Nervous System Disease: Protection from Virus Replication and Antigen Spread and Selection of Epitope Escape Mutants

2004 ◽  
Vol 78 (3) ◽  
pp. 1150-1159 ◽  
Author(s):  
Ming Ming Chua ◽  
Katherine C. MacNamara ◽  
Lani San Mateo ◽  
Hao Shen ◽  
Susan R. Weiss
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Response ◽  
Acute Infection ◽  
T Cell Response ◽  
Cytotoxic T Cell ◽  
Escape Mutants ◽  
The Brain ◽  
Deficient Mice ◽  
Murine Coronavirus

ABSTRACT Both CD4+ and CD8+ T cells are required for clearance of the murine coronavirus mouse hepatitis virus (MHV) during acute infection. We investigated the effects of an epitope-specific CD8+ T-cell response on acute infection of MHV, strain A59, in the murine CNS. Mice with CD8+ T cells specific for gp33-41 (an H-2Db-restricted CD8+ T-cell epitope derived from lymphocytic choriomeningitis glycoprotein) were infected with a recombinant MHV-A59, also expressing gp33-41, as a fusion protein with enhanced green fluorescent protein (EGFP). By 5 days postinfection, these mice showed significantly (approximately 20-fold) lower titers of infectious virus in the brain compared to control mice. Furthermore mice with gp33-41-specific CD8+ cells exhibited much reduced levels of viral antigen in the brain as measured by immunohistochemistry using an antibody directed against viral nucleocapsid. More than 90% of the viruses recovered from brain lysates of such protected mice, at 5 days postinfection, had lost the ability to express EGFP and had deletions in their genomes encompassing EGFP and gp33-41. In addition, genomes of viruses from about half the plaques that retained the EGFP gene had mutations within the gp33-41 epitope. On the other hand, gp33-41-specific cells failed to protect perforin-deficient mice from infection by the recombinant MHV expressing gp33, indicating that perforin-mediated mechanisms were needed. Virus recovered from perforin-deficient mice did not exhibit loss of EGFP expression and the gp33-41 epitope. These observations suggest that the cytotoxic T-cell response to gp33-41 exerts a strong immune pressure that quickly selects epitope escape mutants to gp33-41.

The regulatory T-cell response during acute retroviral infection is locally defined and controls the magnitude and duration of the virus-specific cytotoxic T-cell response

Blood ◽  
2009 ◽  
Vol 114 (15) ◽  
pp. 3199-3207 ◽  
Author(s):  
Gennadiy Zelinskyy ◽  
Kirsten K. Dietze ◽  
Yvonne P. Hüsecken ◽  
Simone Schimmer ◽  
Savita Nair ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Response ◽  
Acute Infection ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Cytotoxic T Cell ◽  
Cell Responses

AbstractCytotoxic CD8+ T cells control acute viremia in many viral infections. However, most viruses that establish chronic infections evade destruction by CD8+ T cells, and regulatory T cells (Treg) are thought to be involved in this immune evasion. We have infected transgenic mice, in which Treg can be selectively depleted, with Friend retrovirus (FV) to investigate the influence of Treg on pathogen-specific CD8+ T-cell responses in vivo. We observed that Treg expansion during acute infection was locally defined to organs with high viral loads and massive activation of virus-specific effector CD8+ T cells. Experimental ablation of Treg resulted in a significant increase of peak cytotoxic CD8+ T-cell responses against FV. In addition, it prevented the development of functional exhaustion of CD8+ T cells and significantly reduced FV loads in lymphatic organs. Surprisingly, despite the massive virus-specific CD8+ T-cell response after temporary Treg depletion, no evidence of immunopathology was found. These results demonstrate the important role of Treg in controlling acute retrovirus-specific CD8+ T-cell responses, and suggest that temporary manipulation of Treg might be a possible therapeutic approach in chronic infectious diseases.

scholarly journals Race between Retroviral Spread and CD4+ T-Cell Response Determines the Outcome of Acute Friend Virus Infection

2009 ◽  
Vol 83 (21) ◽  
pp. 11211-11222 ◽  
Author(s):  
Rebecca Pike ◽  
Andrew Filby ◽  
Mickaël J.-Y. Ploquin ◽  
Urszula Eksmond ◽  
Rute Marques ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Cell Response ◽  
Acute Infection ◽  
T Cell Response ◽  
Friend Virus ◽  
Antiviral Immune Response ◽  
Ultimate Failure ◽  
Necessary And Sufficient

ABSTRACT Retroviruses can establish persistent infection despite induction of a multipartite antiviral immune response. Whether collective failure of all parts of the immune response or selective deficiency in one crucial part underlies the inability of the host to clear retroviral infections is currently uncertain. We examine here the contribution of virus-specific CD4+ T cells in resistance against Friend virus (FV) infection in the murine host. We show that the magnitude and duration of the FV-specific CD4+ T-cell response is directly proportional to resistance against acute FV infection and subsequent disease. Notably, significant protection against FV-induced disease is afforded by FV-specific CD4+ T cells in the absence of a virus-specific CD8+ T-cell or B-cell response. Enhanced spread of FV infection in hosts with increased genetic susceptibility or coinfection with Lactate dehydrogenase-elevating virus (LDV) causes a proportional increase in the number of FV-specific CD4+ T cells required to control FV-induced disease. Furthermore, ultimate failure of FV/LDV coinfected hosts to control FV-induced disease is accompanied by accelerated contraction of the FV-specific CD4+ T-cell response. Conversely, an increased frequency or continuous supply of FV-specific CD4+ T cells is both necessary and sufficient to effectively contain acute infection and prevent disease, even in the presence of coinfection. Thus, these results suggest that FV-specific CD4+ T cells provide significant direct protection against acute FV infection, the extent of which critically depends on the ratio of FV-infected cells to FV-specific CD4+ T cells.

CD8+ T-Cell Responses in Hepatitis B and C: The (HLA-) A, B, and C of Hepatitis B and C

2016 ◽  
Vol 34 (4) ◽  
pp. 396-409 ◽  
Author(s):  
Katja Nitschke ◽  
Hendrik Luxenburger ◽  
Muthamia M. Kiraithe ◽  
Robert Thimme ◽  
Christoph Neumann-Haefelin
Keyword(s):  
T Cells ◽  
T Cell ◽  
Hepatitis B ◽  
Cd8 T Cells ◽  
Cell Response ◽  
Acute Infection ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Hcv Infection ◽  
T Cell Epitopes

Approximately 500 million people are chronically infected with the hepatitis B virus (HBV) or hepatitis C virus (HCV) worldwide and are thus at high risk of progressive liver disease, leading to liver fibrosis, cirrhosis and ultimately hepatocellular cancer. Virus-specific CD8+ T-cells play a major role in viral clearance in >90% of adult patients who clear HBV and in approximately 30% of patients who clear HCV in acute infection. However, several mechanisms contribute to the failure of the adaptive CD8+ T-cell response in those patients who progress to chronic infection. These include viral mutations leading to escape from the CD8+ T-cell response as well as exhaustion and dysfunction of virus-specific CD8+ T-cells. Antiviral efficacy of the virus-specific CD8+ T-cell response also strongly depends on its restriction by specific human leukocyte antigens (HLA) class I alleles. Our review will summarize the role of HLA-A, B and C-restricted CD8+ T-cells in HBV and HCV infection. Due to the current lack of a comprehensive database of HBV- and HCV-specific CD8+ T-cell epitopes, we also provide a summary of the repertoire of currently well-described HBV- and HCV-specific CD8+ T-cell epitopes. A better understanding of the factors that contribute to the success or failure of virus-specific CD8+ T-cells may help to develop new therapeutic options for HBV eradication in patients with chronic HBV infection (therapeutic vaccination and/or immunomodulation) as well as a prophylactic vaccine against HCV infection.

scholarly journals Role of viral infectivity in the induction of influenza virus-specific cytotoxic T cells.

1978 ◽  
Vol 147 (4) ◽  
pp. 1236-1252 ◽  
Author(s):  
T J Braciale ◽  
K L Yap
Keyword(s):  
T Cells ◽  
Influenza Virus ◽  
T Cell ◽  
Cell Response ◽  
Infectious Virus ◽  
Cytotoxic T Cells ◽  
T Cell Response ◽  
Cytotoxic T Cell

This report examines the requirement for infectious virus in the induction of influenza virus-specific cytotoxic T cells. Infectious influenza virus was found to be highly efficient at generating both primary and secondary cytotoxic T-cell response in vivo. Inactivated influenza virus however, failed to stimulate a detectable cytotoxic T-cell response in vivo even at immunizing doses 10(5)-10(6)-fold higher than the minimum stimulatory dose of infectious virus. Likewise inactivated virus failed to sensitize target cells for T cell-mediated lysis in vitro but could stimulate a specific cytotoxic response from primed cells in vitro. Possible requirements for the induction of virus-specific cytotoxic T-cell responses are discussed in light of these observations and those of other investigators.

scholarly journals Loss of Immunization-Induced Epitope-Specific CD4 T-Cell Response following Anaplasma marginale Infection Requires Presence of the T-Cell Epitope on the Pathogen and Is Not Associated with an Increase in Lymphocytes Expressing Known Regulatory Cell Phenotypes

2015 ◽  
Vol 22 (7) ◽  
pp. 742-753 ◽  
Author(s):  
Wendy C. Brown ◽  
Joshua E. Turse ◽  
Paulraj K. Lawrence ◽  
Wendell C. Johnson ◽  
Glen A. Scoles ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Response ◽  
Cell Epitope ◽  
T Cell Response ◽  
T Cell Subsets ◽  
Cd4 T Cell ◽  
Γδ T Cell ◽  
Content Type ◽  
Cell Responses

ABSTRACTWe have shown that in cattle previously immunized with outer membrane proteins, infection withAnaplasma marginaleinduces a functionally exhausted CD4 T-cell response to theA. marginaleimmunogen. Furthermore, T-cell responses following infection in nonimmunized cattle had a delayed onset and were sporadic and transient during persistent infection. The induction of an exhausted T-cell response following infection presumably facilitates pathogen persistence. In the current study, we hypothesized that the loss of epitope-specific T-cell responses requires the presence of the immunizing epitope on the pathogen, and T-cell dysfunction correlates with the appearance of regulatory T cells. In limited studies in cattle, regulatory T cells have been shown to belong to γδ T-cell subsets rather than be CD4 T cells expressing forkhead box protein P3 (FoxP3). Cattle expressing the DRB3*1101 haplotype were immunized with a truncatedA. marginalemajor surface protein (MSP) 1a that contains a DRB3*1101-restricted CD4 T-cell epitope, F2-5B. Cattle either remained unchallenged or were challenged withA. marginalebacteria that express the epitope or withA. marginalesubsp.centralethat do not. Peripheral blood and spleen mononuclear cells were monitored for MSP1a epitope F2-5B-specfic T-cell proliferative responses and were stained for γδ T-cell subsets or CD4+CD25+FoxP3+T cells before and during infection. As hypothesized, the induction of T-cell exhaustion occurred only following infection withA. marginale, which did not correlate with an increase in either CD4+CD25+FoxP3+T cells or any γδ T-cell subset examined.

scholarly journals Diversity of the T-Cell Response to Pulmonary Cryptococcus neoformans Infection

2006 ◽  
Vol 74 (8) ◽  
pp. 4538-4548 ◽  
Author(s):  
Dennis M. Lindell ◽  
Megan N. Ballinger ◽  
Roderick A. McDonald ◽  
Galen B. Toews ◽  
Gary B. Huffnagle
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cryptococcus Neoformans ◽  
Cell Response ◽  
Primary Response ◽  
T Cell Response ◽  
T Cell Subsets ◽  
Lymphoid Tissues ◽  
Cell Mediated Immunity ◽  
Antigen Specificity

ABSTRACT Cell-mediated immunity plays an important role in immunity to the pathogenic fungus Cryptococcus neoformans. However, the antigen specificity of the T-cell response to C. neoformans remains largely unknown. In this study, we used two approaches to determine the antigen specificity of the T-cell response to C. neoformans. We report here that a diverse T-cell receptor (TCR) Vβ repertoire was maintained throughout the primary response to pulmonary C. neoformans infection in immunocompetent mice. CD4+ T-cell deficiency resulted in relative expansion of all CD8+ T-cell subsets. During a secondary immune response, preferential usage of a TCR Vβ subset in CD4+ T cells occurred in single individuals, but the preferences were “private” and not shared between individuals. Both CD4+ and CD8+ T cells from the secondary lymphoid tissues of immunized mice proliferated in response to a variety of C. neoformans antigens, including heat-killed whole C. neoformans, culture filtrate antigen, C. neoformans lysate, and purified cryptococcal mannoprotein. CD4+ and CD8+ T cells from the secondary lymphoid tissues of mice undergoing a primary response to C. neoformans proliferated in response to C. neoformans lysate. In response to stimulation with C. neoformans lysate, lung CD4+ and CD8+ T cells produced the effector cytokines tumor necrosis factor alpha and gamma interferon. These results demonstrate that a diverse T-cell response is generated in response to pulmonary C. neoformans infection.

scholarly journals Reduced Expression of Autophagy Markers and Expansion of Myeloid-Derived Suppressor Cells Correlate With Poor T Cell Response in Severe COVID-19 Patients

2021 ◽  
Vol 12 ◽  
Author(s):  
Sergej Tomić ◽  
Jelena Đokić ◽  
Dejan Stevanović ◽  
Nataša Ilić ◽  
Alisa Gruden-Movsesijan ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Cell Response ◽  
Suppressor Cells ◽  
T Cell Response ◽  
T Cell Subsets ◽  
Myeloid Derived Suppressor Cells ◽  
Immunological Mechanisms

Widespread coronavirus disease (COVID)-19 is causing pneumonia, respiratory and multiorgan failure in susceptible individuals. Dysregulated immune response marks severe COVID-19, but the immunological mechanisms driving COVID-19 pathogenesis are still largely unknown, which is hampering the development of efficient treatments. Here we analyzed ~140 parameters of cellular and humoral immune response in peripheral blood of 41 COVID-19 patients and 16 age/gender-matched healthy donors by flow-cytometry, quantitative PCR, western blot and ELISA, followed by integrated correlation analyses with ~30 common clinical and laboratory parameters. We found that lymphocytopenia in severe COVID-19 patients (n=20) strongly affects T, NK and NKT cells, but not B cells and antibody production. Unlike increased activation of ICOS-1+ CD4+ T cells in mild COVID-19 patients (n=21), T cells in severe patients showed impaired activation, low IFN-γ production and high functional exhaustion, which correlated with significantly down-regulated HLA-DR expression in monocytes, dendritic cells and B cells. The latter phenomenon was followed by lower interferon responsive factor (IRF)-8 and autophagy-related genes expressions, and the expansion of myeloid derived suppressor cells (MDSC). Intriguingly, PD-L1-, ILT-3-, and IDO-1-expressing monocytic MDSC were the dominant producers of IL-6 and IL-10, which correlated with the increased inflammation and accumulation of regulatory B and T cell subsets in severe COVID-19 patients. Overall, down-regulated IRF-8 and autophagy-related genes expression, and the expansion of MDSC subsets could play critical roles in dysregulating T cell response in COVID-19, which could have large implications in diagnostics and design of novel therapeutics for this disease.

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