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Cytomegalovirus infection- and age-dependent changes in human CD8+ T-cell cytokine expression patterns.

ABSTRACT: T cells are strongly affected by immune aging, a phenomenon that leads to increased susceptibility to infections and decreased vaccination efficacy in elderly individuals. Cytomegalovirus (CMV) infection induces vigorous T-cell immune responses in humans and is thought to be a driving force of immune aging. In the present study we analyzed CMV-induced quantitative and qualitative differences in the cytokine-expressing T-cell repertoire from individuals of different age groups after in vitro stimulation. The CMV pp65 peptide pool and the superantigen Staphylococcus enterotoxin B (SEB) induced higher proportions of CD8+ effector T cells expressing gamma interferon (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), and granulocyte-macrophage colony-stimulating factor in the oldest study group, while only SEB induced increased responses in the middle-aged study group. Notably, CMV-specific multiple cytokine expression patterns revealed higher proportions of IFN-gamma- and TNF-alpha-coexpressing CD8+ T cells exclusively in the oldest study group. These qualitative differences were absent in SEB-induced CD8+ effector T cells, although quantitative differences were detected. We report age-dependent qualitative changes in CMV-specific CD8+ T-cell cytokine patterns which are biocandidate markers of immune exhaustion in elderly individuals.

SUBMITTER: Faist B

PROVIDER: S-EPMC2884431 | biostudies-other | 2010 Jun

REPOSITORIES: biostudies-other

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Cytomegalovirus infection- and age-dependent changes in human CD8+ T-cell cytokine expression patterns.

Faist Benjamin B Fleischer Bernhard B Jacobsen Marc M

Clinical and vaccine immunology : CVI 20100428 6

T cells are strongly affected by immune aging, a phenomenon that leads to increased susceptibility to infections and decreased vaccination efficacy in elderly individuals. Cytomegalovirus (CMV) infection induces vigorous T-cell immune responses in humans and is thought to be a driving force of immune aging. In the present study we analyzed CMV-induced quantitative and qualitative differences in the cytokine-expressing T-cell repertoire from individuals of different age groups after in vitro stim ...[more]

PMID: 20427631

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Project description:Reactivation of latent cytomegalovirus (CMV) endangers the therapeutic success of hematopoietic cell transplantation (HCT) in tumor patients due to cytopathogenic virus spread that leads to organ manifestations of CMV disease, to interstitial pneumonia in particular. In cases of virus variants that are refractory to standard antiviral pharmacotherapy, immunotherapy by adoptive cell transfer (ACT) of virus-specific CD8+ T cells is the last resort to bridge the "protection gap" between hematoablative conditioning for HCT and endogenous reconstitution of antiviral immunity. We have used the well-established mouse model of CD8+ T-cell immunotherapy by ACT in a setting of experimental HCT and murine CMV (mCMV) infection to pursue the concept of improving the efficacy of ACT by therapeutic vaccination (TherVac) post-HCT. TherVac aims at restimulation and expansion of limited numbers of transferred antiviral CD8+ T cells within the recipient. Syngeneic HCT was performed with C57BL/6 mice as donors and recipients. Recipients were infected with recombinant mCMV (mCMV-SIINFEKL) that expresses antigenic peptide SIINFEKL presented to CD8+ T cells by the MHC class-I molecule Kb. ACT was performed with transgenic OT-I CD8+ T cells expressing a T-cell receptor specific for SIINFEKL-Kb. Recombinant human CMV dense bodies (DB-SIINFEKL), engineered to contain SIINFEKL within tegument protein pUL83/pp65, served for vaccination. DBs were chosen as they represent non-infectious, enveloped, and thus fusion-competent subviral particles capable of activating dendritic cells and delivering antigens directly into the cytosol for processing and presentation in the MHC class-I pathway. One set of our experiments documents the power of vaccination with DBs in protecting the immunocompetent host against a challenge infection. A further set of experiments revealed a significant improvement of antiviral control in HCT recipients by combining ACT with TherVac. In both settings, the benefit from vaccination with DBs proved to be strictly epitope-specific. The capacity to protect was lost when DBs included the peptide sequence SIINFEKA lacking immunogenicity and antigenicity due to C-terminal residue point mutation L8A, which prevents efficient proteasomal peptide processing and binding to Kb. Our preclinical research data thus provide an argument for using pre-emptive TherVac to enhance antiviral protection by ACT in HCT recipients with diagnosed CMV reactivation.

Project description:Aging population is at higher risk of developing severe COVID-19, including hospitalization and death. In this work, to further understand the relationship between host age-related factors, immunosenescence/exhaustion of the immune system and the response to the virus, we characterized immune cell and cytokine responses in 58 COVID-19 patients admitted to the hospital and 40 healthy controls of different age ranges. Lymphocyte populations and inflammatory profiles were studied in blood samples, using different panels of multicolor flow cytometry. As expected, our analysis reveals differences at both the cellular and cytokine level in COVID-19 patients. Interestingly, when the age range analysis was carried out, the immunological response to the infection was found to differ with age, being especially affected in the group of 30-39 years. In this age range, an increased exhausted T cell response and a decrease of naïve T helper lymphocytes was found in patients, as well as a reduced concentration of the proinflammatory TNF, IL-1β and IL-8 cytokines. Besides, the correlation between age and the study variables was evaluated, and multiple cell types and interleukins were found to correlate with donor age. Notably, the correlations of T helper naïve and effector memory cells, T helper 1-17 cells, TNF, IL-10, IL-1β, IL-8, among others, showed differences between healthy controls and COVID-19 patients. Our findings, in the context of other previous studies, suggest that aging affects the behavior of the immune system in COVID-19 patients. They suggest that young individuals are able to mount an initial response to SARS-CoV-2, but some of them present an accelerated exhaustion of the cell response and an insufficient inflammatory response, resulting in a moderate to severe COVID-19. On the other hand, in older patients there is a smaller immune cell response to the virus, reflected in fewer differences in immune populations between COVID-19 patients and controls. Nevertheless, old patients show more evidence of an inflammatory phenotype, suggesting that the underlying inflammation associated with their age is exacerbated by the SARS-CoV-2 infection.

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Cytomegalovirus infection- and age-dependent changes in human CD8+ T-cell cytokine expression patterns.

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Cytomegalovirus infection- and age-dependent changes in human CD8+ T-cell cytokine expression patterns.

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