Aging and CMV Infection Affect Pre-existing SARS-CoV-2-Reactive CD8+ T Cells in Unexposed Individuals

Jo, Norihide; Zhang, Rui; Ueno, Hideki; Yamamoto, Takuya; Weiskopf, Daniela; Nagao, Miki; Yamanaka, Shinya; Hamazaki, Yoko

doi:10.3389/fragi.2021.719342

Cited by 18 publications

(21 citation statements)

References 72 publications

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“…1A and B). The frequencies of AIM + CD4 + T cells before vaccination, which may include naïve, as well as cross-reactive memory phenotype cells ( 32, 33 ), did not show significant associations with those after vaccination at any time point (Fig. 1C), although a weak correlation was observed after the first dose, which was in agreement with a previous report ( 29 ).…”

Section: Resultssupporting

confidence: 91%

“…Similar to AIM + CD4 + T cells, AIM + CD8 + T-cell induction was significantly delayed in the elderly (Fig. 4A), whereas total CD8 + T cells were unchanged during the monitoring period and those in the elderly were significantly lower than in adults, consistent with a previous report (32). Th1 cells represent another major CD4 + T-cell subset induced by the mRNA vaccine (19,29), with the ability to preferentially produce IFNγ, enhancing CD8 + T-cell function, and favorable for antiviral immunity.…”

Section: Higher Programmed Cell Death Protein-1 (Pd-1) Expression In ...supporting

confidence: 91%

“…Importantly, the findings of the present study suggested a mechanism for the age-related qualitative difference in CD4 + T-cell response: Th1 cells in the elderly tend to express a higher level of PD-1 in response to the mRNA vaccine. Although the CD4 + compartment is relatively well maintained qualitatively and quantitatively compared with CD8 + T cells, especially in humans ( 11, 32 ), several T-cell intrinsic defects, such as T-cell receptor desensitization or epigenetic changes, have been reported ( 52, 53 ). T-cell extrinsic factors, including a defect in antigen-presenting cells with age, were also observed ( 54 ).…”

Section: Discussionmentioning

confidence: 99%

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Delayed antigen-specific CD4⁺ T-cell induction correlates with impaired immune responses to SARS-COV-2 mRNA vaccination in the elderly

Hidaka

Kikuchi

et al. 2022

Preprint

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Despite the clinical efficacy of coronavirus disease 2019 mRNA vaccines, the elderly demonstrate lower IgG levels and neutralizing titers and a higher risk of severe diseases. CD4+ T cells play a central role in regulating antigen-specific antibody and CD8+ T-cell responses; however, because their composition and functionality change significantly with age, relationships between age-associated defects in T cells and the immunogenicity of or reactogenicity to mRNA vaccines are unclear. Using a vaccine cohort (n = 216), we found that the elderly (aged ≥65 years) showed delayed induction and early contraction of vaccine-specific CD4+ T cells, and that the compromised C–X–C motif chemokine receptor 3+ circulating T follicular helper cell response after the first dose was associated with the lower IgG levels. Additionally, the elderly experienced significantly fewer systemic adverse effects (AEs) after the second dose, with those exhibiting few AEs showing lower cytokine+ CD4+ T cells after the first dose and lower antibody levels after the second dose. Furthermore, T helper 1 cells in the elderly expressed higher levels of programmed cell death protein-1, a negative regulator of the T-cell response, which was associated with less production of vaccine-specific CD4+ T cells and impaired CD8+ T-cell expansion. Thus, efficient induction of vaccine-specific effector/memory CD4+ T cells after the first dose may trigger robust cytokine production after the second dose, leading to effective vaccine responses and higher systemic reactogenicity. These results suggested that an enhanced CD4+ T-cell response after the first dose is key to improved vaccination efficacy in the elderly.One Sentence SummaryWe compared immunogenicity and reactogenicity to COVID-19 mRNA vaccine in 107 adults (aged <65 years) and 109 elderly (aged ≥65) individuals.

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Section: Resultssupporting

confidence: 91%

Section: Higher Programmed Cell Death Protein-1 (Pd-1) Expression In ...supporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

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Delayed antigen-specific CD4⁺ T-cell induction correlates with impaired immune responses to SARS-COV-2 mRNA vaccination in the elderly

Hidaka

Kikuchi

et al. 2022

Preprint

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“…Accordingly, impaired cytotoxic CD8 T cell responses have been reported in older COVID-19 patients [ 130 ]. Although SARS-CoV-2-cross reactive CD8 + T cells have been detected in unexposed individuals, this population was found to be decreased in older individuals [ 131 ]. SARS-CoV-2 was also reported to decrease CD4 + helper T cells, specifically in older patients suffering severe COVID-19 disease [ 132 ].…”

Section: Immunosenescence Of Adaptive Immunity and Vaccine Failure In...mentioning

confidence: 99%

How Can We Improve the Vaccination Response in Older People? Part II: Targeting Immunosenescence of Adaptive Immunity Cells

Garnica

Aiello

Ligotti

et al. 2022

IJMS

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The number of people that are 65 years old or older has been increasing due to the improvement in medicine and public health. However, this trend is not accompanied by an increase in quality of life, and this population is vulnerable to most illnesses, especially to infectious diseases. Vaccination is the best strategy to prevent this fact, but older people present a less efficient response, as their immune system is weaker due mainly to a phenomenon known as immunosenescence. The adaptive immune system is constituted by two types of lymphocytes, T and B cells, and the function and fitness of these cell populations are affected during ageing. Here, we review the impact of ageing on T and B cells and discuss the approaches that have been described or proposed to modulate and reverse the decline of the ageing adaptive immune system.

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“…Cytomegalovirus (CMV) is a highly prevalent pathogen and usually induces high T cell frequencies, making CMV a potential source for cross-reactive SARS-CoV-2-specific T cells (Sylwester et al, 2005;Zuhair et al, 2019). This is supported by the finding that SARS-CoV-2 cross-reactive CD8 + T cells have been associated with CMV-seropositive (CMV + ) donors (Alanio et al, 2022;Jo et al, 2021). Moreover, previous CMV infection has been associated with severe COVID-19 thereby suggesting a potential role for these cross-reactive T cells.…”

Section: Introductionmentioning

confidence: 72%

SARS-CoV-2-specific CD4⁺and CD8⁺T cell responses can originate from cross-reactive CMV-specific T cells

Pothast

Dijkland

Thaler

et al. 2022

Preprint

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Detection of SARS-coronavirus-2 (SARS-CoV-2) specific CD4+ and CD8+ T cells in SARS-CoV-2- unexposed donors has been explained by the presence of T cells primed by other coronaviruses. However, based on the relative high frequency and prevalence of cross-reactive T cells, we hypothesized CMV may induce these cross-reactive T cells. Stimulation of pre-pandemic cryo-reserved PBMCs with SARS-CoV-2 peptides revealed that frequencies of SARS-CoV-2-specific T cells were higher in CMV-seropositive donors. Characterization of these T cells demonstrated that membrane-specific CD4+ and spike-specific CD8+ T cells originate from cross-reactive CMV-specific T cells. Spike-specific CD8+ T cells recognize SARS-CoV-2 spike peptide FVSNGTHWF (FVS) and dissimilar CMV pp65 peptide IPSINVHHY (IPS) presented by HLA-B*35:01. These dual IPS/FVS-reactive CD8+ T cells were found in multiple donors and shared a common T cell receptor (TCR), illustrating that IPS/FVS-cross-reactivity is caused by a public TCR. Importantly, these cross-reactive T cells reduced spreading of SARS-CoV-2 in airway epithelial Calu-3 cells yet they were not phenotypically activated during late-stage COVID-19, indicating that cross-reactive T cells may more likely play a role during early stage of infection. In conclusion, CMV-specific T cells cross-react with SARS-CoV-2, despite low sequence homology between the two viruses, and may contribute to the pre-existing immunity against SARS-CoV-2.

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Aging and CMV Infection Affect Pre-existing SARS-CoV-2-Reactive CD8+ T Cells in Unexposed Individuals

Cited by 18 publications

References 72 publications

Delayed antigen-specific CD4⁺ T-cell induction correlates with impaired immune responses to SARS-COV-2 mRNA vaccination in the elderly

Delayed antigen-specific CD4⁺ T-cell induction correlates with impaired immune responses to SARS-COV-2 mRNA vaccination in the elderly

How Can We Improve the Vaccination Response in Older People? Part II: Targeting Immunosenescence of Adaptive Immunity Cells

SARS-CoV-2-specific CD4⁺and CD8⁺T cell responses can originate from cross-reactive CMV-specific T cells

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Aging and CMV Infection Affect Pre-existing SARS-CoV-2-Reactive CD8+ T Cells in Unexposed Individuals

Cited by 18 publications

References 72 publications

Delayed antigen-specific CD4+ T-cell induction correlates with impaired immune responses to SARS-COV-2 mRNA vaccination in the elderly

Delayed antigen-specific CD4+ T-cell induction correlates with impaired immune responses to SARS-COV-2 mRNA vaccination in the elderly

How Can We Improve the Vaccination Response in Older People? Part II: Targeting Immunosenescence of Adaptive Immunity Cells

SARS-CoV-2-specific CD4+and CD8+T cell responses can originate from cross-reactive CMV-specific T cells

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Delayed antigen-specific CD4⁺ T-cell induction correlates with impaired immune responses to SARS-COV-2 mRNA vaccination in the elderly

Delayed antigen-specific CD4⁺ T-cell induction correlates with impaired immune responses to SARS-COV-2 mRNA vaccination in the elderly

SARS-CoV-2-specific CD4⁺and CD8⁺T cell responses can originate from cross-reactive CMV-specific T cells