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

Rafet Basar, Nadima Uprety, Emily Ensley, May Daher, Kimberly Klein, Fernando Martinez, Fleur Aung, Mayra Shanley, Bingqian Hu, Elif Gokdemir, Ana Karen Nunez Cortes, Mayela Mendt, Francia Reyes Silva, Sunil Acharya, Tamara Laskowski, Luis Muniz-Feliciano, Pinaki P. Banerjee, Ye Li, Sufang Li, Luciana Melo GarciaPaul Lin, Hila Shaim, Sean G. Yates, David Marin, Indreshpal Kaur, Sheetal Rao, Duncan Mak, Angelique Lin, Qi Miao, Jinzhuang Dou, Ken Chen, Richard E. Champlin, Elizabeth J. Shpall, Katayoun Rezvani

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Adoptive cell therapy with virus-specific T cells has been used successfully to treat life-threatening viral infections, supporting application of this approach to coronavirus disease 2019 (COVID-19). We expand severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) T cells from the peripheral blood of COVID-19-recovered donors and non-exposed controls using different culture conditions. We observe that the choice of cytokines modulates the expansion, phenotype, and hierarchy of antigenic recognition by SARS-CoV-2 T cells. Culture with interleukin (IL)-2/4/7, but not under other cytokine-driven conditions, results in more than 1,000-fold expansion in SARS-CoV-2 T cells with a retained phenotype, function, and hierarchy of antigenic recognition compared with baseline (pre-expansion) samples. Expanded cytotoxic T lymphocytes (CTLs) are directed against structural SARS-CoV-2 proteins, including the receptor-binding domain of Spike. SARS-CoV-2 T cells cannot be expanded efficiently from the peripheral blood of non-exposed controls. Because corticosteroids are used for management of severe COVID-19, we propose an efficient strategy to inactivate the glucocorticoid receptor gene (NR3C1) in SARS-CoV-2 CTLs using CRISPR-Cas9 gene editing.

Original languageEnglish (US)
Article number109432
JournalCell Reports
Volume36
Issue number3
DOIs
StatePublished - Jul 20 2021
Externally publishedYes

Keywords

  • adoptive cell therapy
  • convalescent plasma
  • CRISPR-Cas9
  • CTL expansion
  • glucocorticoid receptor
  • SARS-CoV-2

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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