Abstract
The detailed characterization of human γδ 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 γδ T cells and a robust mapping method for additional γδ T lymphocytes. Here, we incepted such a method to characterize thousands of γδ 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 γδ tumor-infiltrating T lymphocytes that are more prone to recirculate from the tumor and avoid exhaustion. In COVID-19, both TCRVγ9 and TCRVγnon9 subsets of γδ 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 γδ T lymphocytes in infected lung lesions but not blood, the anti-IL6R therapy with Tocilizumab promotes γδ T lymphocyte differentiation in patients with COVID-19. PBMC from pediatric patients with acute COVID-19 disease display similar γδ T cell lymphopenia to that seen in adult patients. However, blood γδ 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 γδ T lymphocytes durably persist in the blood of adults and could subsequently infiltrate and recirculate in tumors.
Highlights
We downloaded the published scRNAseq dataset from a total of (n = 26) human tumors of head and neck carcinoma (HNSCC), including (n = 8) samples positive and (n = 18) negative for human papillomavirus (HPV), as well as (n = 9) Hodgkin’s lymphoma (HL) of mixed cellularity subtype in which (n = 5) samples were positive and (n = 4) negative for Epstein–Barr virus (EBV). Their respective γδ T lymphocytes were digitally purified, and their TCR subtype and differentiation stage were determined by injection onto the ‘public γδ T cell trajectory’ and cross-labeling with reference gene signatures from external single-cell datasets of human
How explicit time is quantitatively converted into γδ T cell pseudotime remains to be determined, and depends on the transcriptome diversity and the total number of single cells in the dataset
We were able to map and characterize thousands of γδ T lymphocytes from newer datasets onto a formerly-built reference map called here ‘public γδ T cell trajectory’ [28]
Summary
T CD8 TILs in human cancers [28] Overall, these findings raised questions as to whether the viral status of cancer patients affected their γδ TILs, and whether the transcriptomic profiles correlated with those of T lymphocytes from COVID-19 patients’ PBMC. These findings raised questions as to whether the viral status of cancer patients affected their γδ TILs, and whether the transcriptomic profiles correlated with those of T lymphocytes from COVID-19 patients’ PBMC We addressed these questions through a comprehensive characterization of the differentiation and functional hallmarks of γδ T lymphocytes by analyzing scRNAseq datasets of tumors from cancer patients with known viral status, and PBMC from COVID-19 patients
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