Severe COVID-19 triggers robust T cell memory

Recent research has shown that the population of CD8+ T cells targeting SARS-CoV-2 are very diverse. Patients who recover from a severe episode of the novel coronavirus disease (COVID-19) tend to have robust T cell memory responses, as opposed to a more exhausted, restrained repertoire of cells found in those who only developed mild disease.

“Whether these cells play a role in disease pathogenesis or provide long-term immunity is not clear, and further longitudinal analysis and function studies in relevant model organisms are required to clarify this,” the researchers said.

Using a modified antigen-reactive T cell enrichment assay, the single-cell transcriptomes of >80,000 CD8+ memory T cells were assessed. Samples were obtained from 39 COVID-19 patients—17 with mild disease, 13 requiring hospitalization, and nine admitted into intensive care—and 10 healthy, nonexposed controls.

Transcriptomic analysis of tall viral-reactive T cells yielded eight distinct clusters, suggesting that CD8+ memory cells were able to activate a variety of transcriptional pathways in response to viral challenge. [Sci Immunol 2021;6:eabe4782]

Among these clusters, one comprised <1 percent of all cells and was subsequently removed from the analysis. Another cluster was enriched with a set of signature genes that indicated exhaustion of the CD8+ T cells. These lymphocytes tended to display altered or limited functionality in protecting host tissue, or complete lack thereof.

In turn, these cells may weaken the memory response to SARS-CoV-2 infection. There was a significant but inverse correlation between the absolute virus-reactive memory CD8+ T cells in circulation and the proportion of cells in the exhausted cluster.

Notably, the researchers saw that around 30 percent of COVID-19 patients mounted a majority exhausted CD8+ T cell memory response in the face of SARS-CoV-2 infection. Those with milder disease also tended to launch a significantly greater proportion of these exhausted cells, as opposed to comparators with severe disease.

Response in patients with severe disease, on the other hand, tended to have strong cytotoxicity, accompanied by depletions in interferon genes and upregulations in exhaustion signatures.

“It is possible that patients with severe disease might develop a stronger ‘exhaustion’ programme as a compensatory mechanism to make up for their depleted quantity of protective ‘exhausted’ cells to prevent further immunopathology while retaining their core cytotoxic functionality,” the researchers explained.

Even among patients without the predominantly exhausted CD8+ T cell repertoire, notable differences between severe and mild COVID-19 were apparent. Ingenuity Pathway Analysis showed that survivors of severe disease saw an enrichment of transcripts from co-stimulation and NF-κB pathways.

“Co-stimulation is required for the robust activation and generation of memory T cell responses,” the researchers explained, while “the activation of the NF-κB pathway has been shown to be important for T cell interleukin-2 production, proliferation, survival, cytokine production, and effector function.” [Cold Spring Harb Perspect Biol 2010;2:a000182; Crit Rev Immunol 2009;29:469-486]

Patients who had severe COVID-19 also saw stronger signals for cell fitness, cytokine production, cytotoxic T cell generation, viral clearance, and cell survival, among others.

“Overall, our findings suggested that SARS-CoV-2-reactive CD8+ T cells from patients with severe COVID-19 displayed multiple features that support the generation of robust CD8+ T cell memory responses with pro-survival properties,” the researchers said.