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

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.

γδ T Cells in Emerging Viral Infection: An Overview

“…Interestingly, the authors demonstrated that γδ T cells (Vγ9 and non-Vγ9) of severe COVID-19 adult patients are recruited in the lesions of the lung from peripheral blood and showed an effector/exhausted phenotype. In addition, in pediatric acute COVID-19 patients, the authors observed a γδ T-cell lymphopenia similar to the adult patients [55].…”

Single-cell differentiation trajectories define early stages of a human cutaneous T-cell lymphoma

“…This trajectory also constitutes a reference roadmap onto which ab extra γδ T cells from any additional scRNAseq datasets can now be positioned such as to identify their hallmarks. The γδ T cells infiltrating human tumors, and those from blood or lung lesions of COVID-19 patients were characterized accordingly [3]. Likewise, mapping of γδ T cells extracted from a human γδ T cell lymphoma scRNAseq dataset had never been attempted, however, and the present study reports its successful use for characterizing CTCL of γδ T lineage.…”

“…We further refined the transcriptomic transitions underlying this differentiation by delineating 14 successive milestones from the Tn to Temra cells as visualized in a pseudotime-based trajectory [2]. The differentiation stages of γδ T lymphocytes in patients with cancers or with coronavirus disease 2019 (COVID-19) were characterized accordingly and unveiled the association of circulating γδ T lymphocytes with the viral status of individuals [3]. These studies illustrated the power and resolution achieved by trajectory mapping for normal γδ T lymphocytes, but its potential for characterizing the differentiation of malignant γδ T cells was unknown.…”

Role of hormones in the pregnancy and sex‐specific outcomes to infections with respiratory viruses*

“…233 This subset may also form a part of the immune response to SARS-CoV-2, localizing to the lung from peripheral blood and persist as tissue-resident memory-like cells. 234 However, a study has shown that γδ T cell populations decrease during SARS-CoV-2 infection, possibly a result of exhaustion. 235 However, most studies outline a transitional role for γδ T cell subsets as they aid in implantation via inflammation and must quickly…”

“…Earlier work with SARS‐CoV‐1 identified that IFN‐γ+ Vγ9Vδ2 T cells were an important portion of the effector memory T cell response to SARS‐CoV‐1 233 . This subset may also form a part of the immune response to SARS‐CoV‐2, localizing to the lung from peripheral blood and persist as tissue‐resident memory‐like cells 234 . However, a study has shown that γδ T cell populations decrease during SARS‐CoV‐2 infection, possibly a result of exhaustion 235 …”