Single-Cell RNAseq Profiling of Human γδ T Lymphocytes in Virus-Related Cancers and COVID-19 Disease

The detailed characterization of human gamma delta T lymphocyte differentiation at the single-cell transcriptomic (scRNAseq) level in tumors and patients with coronavirus disease 2019 (COVID-19) requires both a reference differentiation trajectory of gamma delta T cells and a robust mapping method for additional gamma delta T lymphocytes. Here, we incepted such a method to characterize thousands of gamma delta T lymphocytes from (n = 95) patients with cancer or adult and pediatric COVID-19 disease. We found that cancer patients with human papillomavirus-positive head and neck squamous cell carcinoma and Epstein-Barr virus-positive Hodgkin's lymphoma have gamma delta tumor-infiltrating T lymphocytes that are more prone to recirculate from the tumor and avoid exhaustion. In COVID-19, both TCRV gamma 9 and TCRV gamma non9 subsets of gamma delta T lymphocytes relocalize from peripheral blood mononuclear cells (PBMC) to the infected lung tissue, where their advanced differentiation, tissue residency, and exhaustion reflect T cell activation. Although severe COVID-19 disease increases both recruitment and exhaustion of gamma delta T lymphocytes in infected lung lesions but not blood, the anti-IL6R therapy with Tocilizumab promotes gamma delta T lymphocyte differentiation in patients with COVID-19. PBMC from pediatric patients with acute COVID-19 disease display similar gamma delta T cell lymphopenia to that seen in adult patients. However, blood gamma delta T cells from children with the COVID-19-related multisystem inflammatory syndrome are not lymphodepleted, but they are differentiated as in healthy PBMC. These findings suggest that some virus-induced memory gamma delta T lymphocytes durably persist in the blood of adults and could subsequently infiltrate and recirculate in tumors.

Automated summary

The study characterized the differentiation of human gamma delta T lymphocytes in tumors and COVID-19 patients at the single-cell transcriptomic level. It found that tumor-infiltrating gamma delta T cells in certain cancer patients were more likely to recirculate and avoid exhaustion, while in COVID-19 patients, gamma delta T cells relocated to infected lung tissue displaying different differentiation, tissue residency, and exhaustion patterns.