Ageing Curtails the Diversity and Functionality of Nascent CD8+ T Cell Responses against SARS-CoV-2.

Age-related changes in the immune system are thought to underlie the vulnerability of elderly individuals to emerging viral diseases, such as coronavirus disease 2019 (COVID-19). In this study, we used a fully validated in vitro approach to determine how age impacts the generation of de novo CD8+ T cell responses against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of COVID-19. Our data revealed a generalized deficit in the ability of elderly individuals to prime the differentiation of naïve precursors into effector CD8+ T cells defined by the expression of interferon (IFN)-γ and the transcription factor T-bet. As a consequence, there was an age-related decline in the diversity of newly generated CD8+ T cell responses targeting a range of typically immunodominant epitopes derived from SARS-CoV-2, accompanied by an overall reduction in the expression frequency of IFN-γ. These findings have potential implications for the development of new strategies to protect the elderly against COVID-19.

Time Trend Analysis of Tuberculosis Treatment While Using Digital Adherence Technologies—An Individual Patient Data Meta-Analysis of Eleven Projects across Ten High Tuberculosis-Burden Countries

Worldwide, non-adherence to tuberculosis (TB) treatment is problematic. Digital adherence technologies (DATs) offer a person-centered approach to support and monitor treatment. We explored adherence over time while using DATs. We conducted a meta-analysis on anonymized longitudinal adherence data for drug-susceptible (DS) TB (n = 4515) and drug-resistant (DR) TB (n = 473) populations from 11 DAT projects. Using Tobit regression, we assessed adherence for six months of treatment across sex, age, project enrolment phase, DAT-type, health care facility (HCF), and project. We found that DATs recorded high levels of adherence throughout treatment: 80% to 71% of DS-TB patients had ≥90% adherence in month 1 and 6, respectively, and 73% to 75% for DR-TB patients. Adherence increased between month 1 and 2 (DS-TB and DR-TB populations), then decreased (DS-TB). Males displayed lower adherence and steeper decreases than females (DS-TB). DS-TB patients aged 15–34 years compared to those >50 years displayed steeper decreases. Adherence was correlated within HCFs and differed between projects. TB treatment adherence decreased over time and differed between subgroups, suggesting that over time, some patients are at risk for non-adherence. The real-time monitoring of medication adherence using DATs provides opportunities for health care workers to identify patients who need greater levels of adherence support.

Altered Basal Lipid Metabolism Underlies the Functional Impairment of Naive CD8+ T Cells in Elderly Humans.

Aging is associated with functional deficits in the naive T cell compartment, which compromise the generation of de novo immune responses against previously unencountered Ags. The mechanisms that underlie this phenomenon have nonetheless remained unclear. We found that naive CD8+ T cells in elderly humans were prone to apoptosis and proliferated suboptimally in response to stimulation via the TCR. These abnormalities were associated with dysregulated lipid metabolism under homeostatic conditions and enhanced levels of basal activation. Importantly, reversal of the bioenergetic anomalies with lipid-altering drugs, such as rosiglitazone, almost completely restored the Ag responsiveness of naive CD8+ T cells. Interventions that favor lipid catabolism may therefore find utility as adjunctive therapies in the elderly to promote vaccine-induced immunity against targetable cancers and emerging pathogens, such as seasonal influenza viruses and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Impaired Priming of SARS-CoV-2-Specific Naive CD8+ T Cells in Older Subjects.

Advanced age is associated with severe symptoms and death upon SARS-CoV-2 infection. Virus-specific CD8+ T-cell responses have shown to be protective toward critical COVID-19 manifestations, suggesting that suboptimal cellular immunity may contribute to the age-pattern of the disease. The induction of a CD8+ T-cell response against an emerging pathogen like SARS-CoV-2 relies on the activation of naive T cells. To investigate whether the primary CD8+ T-cell response against this virus is defective in advanced age, we used an in vitro approach to prime SARS-CoV-2-specific naive CD8+ T cells from healthy, unexposed donors of different age groups. Compared to younger adults, older individuals display a poor SARS-CoV-2-specific T-cell priming capacity in terms of both magnitude and quality of the response. In addition, older subjects recognize a lower number of epitopes. Our results implicate that immune aging is associated with altered primary SARS-CoV-2-specific CD8+ T-cell responses.