Impaired cytotoxic CD8+ T cell response in elderly COVID-19 patients
Cardiff University review T cell
First Author: Jaana Westmeier
Journal/preprint name: BioRxiv
Paper DOI: doi.org/10.1101/2020.08.21.262329
Tags: elderly, CD8 T cells, cytotoxic, dysfunction, granzyme, perforin, PD-1
Many previous studies have showed age-related disease severity and mortality outcomes in COVID-19 disease, which appear to be associated with dysfunctional T cell responses. This study shows that the cytotoxic T cell response in COVID-19 is mediated by CD8+ T cells, with negligible contribution from CD4+ T cells. However, the cytotoxic response is impaired in older patients, characterised by depletion of CD8+ T cells, lack of expansion of effector phenotypes and no increase in the production of cytotoxic effector molecules. Since these data were obtained a mild cohort, further data on cytotoxic responses in severe COVID-19 is warranted.
CD4+ T cells were reduced compared to healthy controls but did not show an age-related decrease in COVID-19 patients. Contrastingly, CD8+ T cells were reduced compared to healthy controls in both age groups, but also in patients aged >80 years compared to younger COVID-19 patients.
Unsurprisingly, controls aged 80-96 had higher frequencies of terminally differentiated effector (TEM) and lower frequencies of naïve CD8+ T cells than controls aged <80 years. However, proportions of these phenotypes were not altered in COVID-19 patients aged 80-96, nor did the production of cytotoxic effector molecules increase.
Patients aged <80 demonstrated an ongoing CD8+ T cell response, characterised by increased TEM and effector memory (EM) and slightly reduced naïve CD8+ T cell frequencies compared to age-matched controls. CD8+ T cells in this cohort produced significantly more cytotoxic effector molecules (granzymes A and B and perforin) compared to age matched controls.
PD-1 expressing CD8+ T cells in patients of all ages produced granzyme A, although only patients aged 29-79 produced significantly more granzyme B and perforin than age-matched controls.
The majority of TEM and EM CD8+ T cells in patients of all ages produced at least two of granzymes A, B or perforin; it is unknown whether polyfunctional cytotoxic effector molecule production is protective or contributes to immunopathology.
Impact for COVID-19 research:
The impairment of cytotoxic T cell responses in elderly COVID-19 patients is likely to contribute to poorer infection control and greater disease severity in association with age. However, more in-depth characterisation of the T cells in association with differing disease severities/ trajectories is required to support these conclusions.
Study Type: Age matched case-control study of acute mild COVID-19 disease.
Key Techniques: PBMC directly isolated from patient blood and analysed by flow cytometry without ex-vivo stimulation. Clone and manufacturer information for the antibodies used are provided.
Relatively small study (n=30). Cohort numbers could be more clearly described in figures and supplementary data is missing.
Since the study included only mild cases, it is not possible to correlate the reduced cytotoxic response in the elderly patients to disease severity.
Phenotyping of the T cells was relatively limited; by comparison other studies have highlighted increased frequencies of CD4+ or CD8+ T cells expressing activation markers HLA-DR and CD38 (Mathew et al., 2020, Kuri-Cervantes et al., 2020) and cytokines e.g. IFNg (Chen et al., 2020).