scholarly journals SARS-CoV-2 specific T cell responses are lower in children and increase with age and time after infection

2021 ◽  
Author(s):  
Carolyn A Cohen ◽  
Athena PY Li ◽  
Asmaa Hachim ◽  
David SC Hui ◽  
Mike YW Kwan ◽  
...  
Keyword(s):  
T Cell ◽  
Antigen Processing ◽  
De Novo ◽  
Acute Infection ◽  
T Cell Responses ◽  
Effector Memory ◽  
Long Term Memory ◽  
Symptomatic Infection ◽  
Cell Responses ◽  
Time Post Infection

AbstractSARS-CoV-2 infection of children leads to a mild illness and the immunological differences with adults remains unclear. We quantified the SARS-CoV-2 specific T cell responses in adults and children (<13 years of age) with RT-PCR confirmed asymptomatic and symptomatic infection for long-term memory, phenotype and polyfunctional cytokines. Acute and memory CD4+ T cell responses to structural SARS-CoV-2 proteins significantly increased with age, whilst CD8+ T cell responses increased with time post infection. Infected children had significantly lower CD4+ and CD8+ T cell responses to SARS-CoV-2 structural and ORF1ab proteins compared to infected adults. SARS-CoV-2-specific CD8+ T cell responses were comparable in magnitude to uninfected negative adult controls. In infected adults CD4+ T cell specificity was skewed towards structural peptides, whilst children had increased contribution of ORF1ab responses. This may reflect differing T cell compartmentalisation for antigen processing during antigen exposure or lower recruitment of memory populations. T cell polyfunctional cytokine production was comparable between children and adults, but children had a lower proportion of SARS-CoV-2 CD4+ T cell effector memory. Compared to adults, children had significantly lower levels of antibodies to β-coronaviruses, indicating differing baseline immunity. Total T follicular helper responses was increased in children during acute infection indicating rapid co-ordination of the T and B cell responses. However total monocyte responses were reduced in children which may be reflective of differing levels of inflammation between children and adults. Therefore, reduced prior β-coronavirus immunity and reduced activation and recruitment of de novo responses in children may drive milder COVID-19 pathogenesis.

scholarly journals SARS-CoV-2 specific T cell responses are lower in children and increase with age and time after infection

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Carolyn A. Cohen ◽  
Athena P. Y. Li ◽  
Asmaa Hachim ◽  
David S. C. Hui ◽  
Mike Y. W. Kwan ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
T Cell Responses ◽  
Effector Memory ◽  
Cell Responses ◽  
Follicular Helper ◽  
Time Post Infection ◽  
Adults And Children ◽  
Cell Effector

AbstractSARS-CoV-2 infection of children leads to a mild illness and the immunological differences with adults are unclear. Here, we report SARS-CoV-2 specific T cell responses in infected adults and children and find that the acute and memory CD4+ T cell responses to structural SARS-CoV-2 proteins increase with age, whereas CD8+ T cell responses increase with time post-infection. Infected children have lower CD4+ and CD8+ T cell responses to SARS-CoV-2 structural and ORF1ab proteins when compared with infected adults, comparable T cell polyfunctionality and reduced CD4+ T cell effector memory. Compared with adults, children have lower levels of antibodies to β-coronaviruses, indicating differing baseline immunity. Total T follicular helper responses are increased, whilst monocyte numbers are reduced, indicating rapid adaptive co-ordination of the T and B cell responses and differing levels of inflammation. Therefore, reduced prior β-coronavirus immunity and reduced T cell activation in children might drive milder COVID-19 pathogenesis.

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 B cell depletion impairs vaccination-induced CD8+ T cell responses in a type I interferon-dependent manner

2021 ◽  
pp. annrheumdis-2021-220435
Author(s):  
Theresa Graalmann ◽  
Katharina Borst ◽  
Himanshu Manchanda ◽  
Lea Vaas ◽  
Matthias Bruhn ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cell Expansion ◽  
De Novo ◽  
T Cell Responses ◽  
Type I ◽  
Cell Responses ◽  
T Cell Expansion

ObjectivesThe monoclonal anti-CD20 antibody rituximab is frequently applied in the treatment of lymphoma as well as autoimmune diseases and confers efficient depletion of recirculating B cells. Correspondingly, B cell-depleted patients barely mount de novo antibody responses during infections or vaccinations. Therefore, efficient immune responses of B cell-depleted patients largely depend on protective T cell responses.MethodsCD8+ T cell expansion was studied in rituximab-treated rheumatoid arthritis (RA) patients and B cell-deficient mice on vaccination/infection with different vaccines/pathogens.ResultsRituximab-treated RA patients vaccinated with Influvac showed reduced expansion of influenza-specific CD8+ T cells when compared with healthy controls. Moreover, B cell-deficient JHT mice infected with mouse-adapted Influenza or modified vaccinia virus Ankara showed less vigorous expansion of virus-specific CD8+ T cells than wild type mice. Of note, JHT mice do not have an intrinsic impairment of CD8+ T cell expansion, since infection with vaccinia virus induced similar T cell expansion in JHT and wild type mice. Direct type I interferon receptor signalling of B cells was necessary to induce several chemokines in B cells and to support T cell help by enhancing the expression of MHC-I.ConclusionsDepending on the stimulus, B cells can modulate CD8+ T cell responses. Thus, B cell depletion causes a deficiency of de novo antibody responses and affects the efficacy of cellular response including cytotoxic T cells. The choice of the appropriate vaccine to vaccinate B cell-depleted patients has to be re-evaluated in order to efficiently induce protective CD8+ T cell responses.

scholarly journals Robust SARS-CoV-2-specific T-cell immunity is maintained at 6 months following primary infection

2020 ◽  
Author(s):  
Jianmin Zuo ◽  
Alex Dowell ◽  
Hayden Pearce ◽  
Kriti Verma ◽  
Heather Long ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Immune Responses ◽  
Antibody Level ◽  
Primary Infection ◽  
Natural Infection ◽  
T Cell Responses ◽  
Symptomatic Infection ◽  
Cell Responses ◽  
Cell Immunity

Abstract The immune response to SARS-CoV-2 is critical in both controlling primary infection and preventing re-infection. However, there is concern that immune responses following natural infection may not be sustained and that this may predispose to recurrent infection. We analysed the magnitude and phenotype of the SARS-CoV-2 cellular immune response in 100 donors at six months following primary infection and related this to the profile of antibody level against spike, nucleoprotein and RBD over the previous six months. T-cell immune responses to SARS-CoV-2 were present by ELISPOT or ICS analysis in all donors and are characterised by predominant CD4+ T cell responses with strong IL-2 cytokine expression. Median T-cell responses were 50% higher in donors who had experienced an initial symptomatic infection indicating that the severity of primary infection establishes a ‘setpoint’ for cellular immunity that lasts for at least 6 months. The T-cell responses to both spike and nucleoprotein/membrane proteins were strongly correlated with the peak antibody level against each protein. The rate of decline in antibody level varied between individuals and higher levels of nucleoprotein-specific T cells were associated with preservation of NP-specific antibody level although no such correlation was observed in relation to spike-specific responses. In conclusion, our data are reassuring that functional SARS-CoV-2-specific T-cell responses are retained at six months following infection although the magnitude of this response is related to the clinical features of primary infection.

scholarly journals Mononucleosis and Antigen-Driven T Cell Responses Have Different Requirements for Interleukin-2 Signaling in Murine Gammaherpesvirus Infection

2010 ◽  
Vol 84 (20) ◽  
pp. 10923-10927 ◽  
Author(s):  
Michael Molloy ◽  
Weijun Zhang ◽  
Edward Usherwood
Keyword(s):  
T Cell ◽  
Cell Response ◽  
Interleukin 2 ◽  
T Cell Responses ◽  
T Cell Response ◽  
Long Term Memory ◽  
Murine Gammaherpesvirus ◽  
Cell Responses ◽  
Gammaherpesvirus 68 ◽  
Murine Gammaherpesvirus 68

ABSTRACT Interleukin-2 (IL-2) has been implicated as being necessary for the optimal formation of primary CD8+ T cell responses against various pathogens. Here we have examined the role that IL-2 signaling plays in several aspects of a CD8+ T cell response against murine gammaherpesvirus 68 (MHV-68). Exposure to MHV-68 causes a persistent infection, along with infectious mononucleosis, providing a model for studying these processes in mice. Our study indicates that CD25 is necessary for optimal expansion of the antigen-specific CD8+ T cell response but not for the long-term memory response. Contrastingly, IL-2 signaling through CD25 is absolutely required for CD8+ T cell mononucleosis.

scholarly journals Optimising T cell (re)boosting strategies for adenoviral and modified vaccinia Ankara vaccine regimens in humans

npj Vaccines ◽  
2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Stefania Capone ◽  
Anthony Brown ◽  
Felicity Hartnell ◽  
Mariarosaria Del Sorbo ◽  
Cinzia Traboni ◽  
...  
Keyword(s):  
T Cells ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
T Cell ◽  
Viral Vectors ◽  
Standard Dose ◽  
T Cell Responses ◽  
Effector Memory ◽  
Cell Responses ◽  
Wide Range

Abstract Simian adenoviral and modified vaccinia Ankara (MVA) viral vectors used in heterologous prime-boost strategies are potent inducers of T cells against encoded antigens and are in advanced testing as vaccine carriers for a wide range of infectious agents and cancers. It is unclear if these responses can be further enhanced or sustained with reboosting strategies. Furthermore, despite the challenges involved in MVA manufacture dose de-escalation has not been performed in humans. In this study, healthy volunteers received chimpanzee-derived adenovirus-3 and MVA vaccines encoding the non-structural region of hepatitis C virus (ChAd3-NSmut/MVA-NSmut) 8 weeks apart. Volunteers were then reboosted with a second round of ChAd3-NSmut/MVA-NSmut or MVA-NSmut vaccines 8 weeks or 1-year later. We also determined the capacity of reduced doses of MVA-NSmut to boost ChAd3-NSmut primed T cells. Reboosting was safe, with no enhanced reactogenicity. Reboosting after an 8-week interval led to minimal re-expansion of transgene-specific T cells. However, after a longer interval, T cell responses expanded efficiently and memory responses were enhanced. The 8-week interval regimen induced a higher percentage of terminally differentiated and effector memory T cells. Reboosting with MVA-NSmut alone was as effective as with ChAd3-NSmut/MVA-NSmut. A ten-fold lower dose of MVA (2 × 107pfu) induced high-magnitude, sustained, broad, and functional Hepatitis C virus (HCV)-specific T cell responses, equivalent to standard doses (2 × 108 pfu). Overall, we show that following Ad/MVA prime-boost vaccination reboosting is most effective after a prolonged interval and is productive with MVA alone. Importantly, we also show that a ten-fold lower dose of MVA is as potent in humans as the standard dose.

scholarly journals Suppression of Acute Anti-Friend Virus CD8+ T-Cell Responses by Coinfection with Lactate Dehydrogenase-Elevating Virus

2007 ◽  
Vol 82 (1) ◽  
pp. 408-418 ◽  
Author(s):  
Shelly J. Robertson ◽  
Christoph G. Ammann ◽  
Ronald J. Messer ◽  
Aaron B. Carmody ◽  
Lara Myers ◽  
...  
Keyword(s):  
Lactate Dehydrogenase ◽  
T Cell ◽  
T Regulatory Cells ◽  
Acute Infection ◽  
T Cell Responses ◽  
Host Responses ◽  
Delayed Response ◽  
Friend Virus ◽  
Chronic Infections ◽  
Cell Responses

ABSTRACT Friend virus (FV) and lactate dehydrogenase-elevating virus (LDV) are endemic mouse viruses that can cause long-term chronic infections in mice. We found that numerous mouse-passaged FV isolates also contained LDV and that coinfection with LDV delayed FV-specific CD8+ T-cell responses during acute infection. While LDV did not alter the type of acute pathology induced by FV, which was severe splenomegaly caused by erythroproliferation, the immunosuppression mediated by LDV increased both the severity and the duration of FV infection. Compared to mice infected with FV alone, those coinfected with both FV and LDV had delayed CD8+ T-cell responses, as measured by FV-specific tetramers. This delayed response accounted for the prolonged and exacerbated acute phase of FV infection. Suppression of FV-specific CD8+ T-cell responses occurred not only in mice infected concomitantly with LDV but also in mice chronically infected with LDV 8 weeks prior to infection with FV. The LDV-induced suppression was not mediated by T regulatory cells, and no inhibition of the CD4+ T-cell or antibody responses was observed. Considering that most human adults are carriers of chronically infectious viruses at the time of new virus insults and that coinfections with viruses such as human immunodeficiency virus and hepatitis C virus are currently epidemic, it is of great interest to determine how infection with one virus may impact host responses to a second infection. Coinfection of mice with LDV and FV provides a well-defined, natural host model for such studies.

scholarly journals Enhanced T Cell Responses Induced by a Necrotic Dendritic Cell Vaccine, Expressing HCV NS3

2020 ◽  
Vol 11 ◽  
Author(s):  
Zelalem A. Mekonnen ◽  
Makutiro G. Masavuli ◽  
Wenbo Yu ◽  
Jason Gummow ◽  
Dawn M. Whelan ◽  
...  
Keyword(s):  
T Cell ◽  
Vaccination Strategy ◽  
T Cell Responses ◽  
Dendritic Cell Vaccine ◽  
Effector Memory ◽  
Cell Vaccine ◽  
Cell Mediated Immunity ◽  
Structural Protein ◽  
Cell Responses ◽  
Dc Vaccine

A vaccine that induces potent, broad and sustained cell-mediated immunity, resulting in effective memory has the potential to restrict hepatitis C (HCV) virus infection. Early, multi-functional CD4+ and CD8+ T cell responses against non-structural protein 3 (NS3) have been associated with HCV clearance. Necrotic cells generate strong immune responses and represent a major antigenic source used by dendritic cells (DC) for processing and presentation, but there is conflicting evidence as to their immunogenicity in vaccination. Immunization with DC loaded with viral antigens has been done in the past, but to date the immunogenicity of live vs. necrotic DC vaccines has not been investigated. We developed a DC2.4 cell line stably expressing HCV NS3, and compared the NS3-specific responses of live vs. necrotic NS3 DC. Vaccination of mice with necrotic NS3 DC increased the breadth of T-cell responses and enhanced the production of IL-2, TNF-α, and IFN-γ by effector memory CD4+ and CD8+T cells, compared to mice vaccinated with live NS3 DC. A single dose of necrotic NS3 DC vaccine induced a greater influx and activation of cross-presenting CD11c+ CD8α+ DC and necrosis-sensing Clec9A+ DC in the draining lymph nodes. Furthermore, using a hydrodynamic challenge model necrotic NS3 DC vaccination resulted in enhanced clearance of NS3-positive hepatocytes from the livers of vaccinated mice. Taken together, the data demonstrate that necrotic DC represent a novel and exciting vaccination strategy capable of inducing broad and multifunctional T cell memory.

scholarly journals Characterization of local and circulating bovine γδ T cell responses to respiratory BCG vaccination

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Mariana Guerra-Maupome ◽  
Jodi L. McGill
Keyword(s):  
T Cells ◽  
T Cell ◽  
Γδ T Cells ◽  
T Cell Responses ◽  
Memory Cell ◽  
Effector Memory ◽  
Γδ T Cell ◽  
Respiratory Mucosa ◽  
Bcg Vaccination ◽  
Cell Responses

Abstract The Mycobacterium bovis Bacillus Calmette-Guerin (BCG) vaccine is administered parenterally to infants and young children to prevent tuberculosis (TB) infection. However, the protection induced by BCG is highly variable and the vaccine does not prevent pulmonary TB, the most common form of the illness. Until improved TB vaccines are available, it is crucial to use BCG in a manner which ensures optimal vaccine performance. Immunization directly to the respiratory mucosa has been shown to promote greater protection from TB in animal models. γδ T cells play a major role in host defense at mucosal sites and are known to respond robustly to mycobacterial infection. Their positioning in the respiratory mucosa ensures their engagement in the response to aerosolized TB vaccination. However, our understanding of the effect of respiratory BCG vaccination on γδ T cell responses in the lung is unknown. In this study, we used a calf model to investigate the immunogenicity of aerosol BCG vaccination, and the phenotypic profile of peripheral and mucosal γδ T cells responding to vaccination. We observed robust local and systemic M. bovis-specific IFN-γ and IL-17 production by both γδ and CD4 T cells. Importantly, BCG vaccination induced effector and memory cell differentiation of γδ T cells in both the lower airways and peripheral blood, with accumulation of a large proportion of effector memory γδ T cells in both compartments. Our results demonstrate the potential of the neonatal calf model to evaluate TB vaccine candidates that are to be administered via the respiratory tract, and suggest that aerosol immunization is a promising strategy for engaging γδ T cells in vaccine-induced immunity against TB.

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