Impaired cytotoxic CD8+ T cell response in elderly COVID-19 patients

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.  

Research Highlights  

1. 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. 

2. 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. 

3. 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. 

4. 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.  

5. 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. 

Methodologies: 

• 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. 

Limitations: 

• 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).