Generation of glucocorticoid resistant SARS-CoV-2 T-cells for adoptive cell therapy

SUMMARY
Adoptive cell therapy with viral-specific T cells has been successfully used to treat life-threatening viral infections, supporting the application of this approach against COVID-19. We expanded SARS-CoV-2 T-cells from the peripheral blood of COVID-19-recovered donors and non-exposed controls using different culture conditions. We observed that the choice of cytokines modulates the expansion, phenotype and hierarchy of antigenic recognition by SARS-CoV-2 T-cells. Culture with IL-2/4/7 but not other cytokine-driven conditions resulted in >1000 fold expansion in SARS-CoV-2 T-cells with a retained phenotype, function and hierarchy of antigenic recognition when compared to baseline (pre-expansion) samples. Expanded CTLs were directed against structural SARS-CoV-2 proteins, including the receptor-binding domain of Spike. SARS-CoV-2 T-cells could not be efficiently expanded from the peripheral blood of non-exposed controls. Since corticosteroids are used for the management of severe COVID-19, we developed an efficient strategy to inactivate the glucocorticoid receptor gene (NR3C1) in SARS-CoV-2 CTLs using CRISPR-Cas9 gene editing.
Competing Interest Statement
The authors have declared no competing interest.
Subject Area
- Biochemistry (9171)
- Bioengineering (6804)
- Bioinformatics (24062)
- Biophysics (12154)
- Cancer Biology (9564)
- Cell Biology (13824)
- Clinical Trials (138)
- Developmental Biology (7656)
- Ecology (11736)
- Epidemiology (2066)
- Evolutionary Biology (15540)
- Genetics (10670)
- Genomics (14358)
- Immunology (9511)
- Microbiology (22901)
- Molecular Biology (9129)
- Neuroscience (49107)
- Paleontology (357)
- Pathology (1487)
- Pharmacology and Toxicology (2583)
- Physiology (3851)
- Plant Biology (8351)
- Synthetic Biology (2301)
- Systems Biology (6205)
- Zoology (1302)