Single-cell RNA sequencing unveils the shared and the distinct cytotoxic hallmarks of human TCRVδ1 and TCRVδ2 γδ T lymphocytes

Gabriele Pizzolato, Francesco Dieli, Serena Meraviglia, Don-Marc Franchini, Marie Tosolini, Carine Valle, Mary Poupot, Camille Laurent, Pierre Milpied, Hannah Kaminski, Fréderic Martins, Anne Quillet-Mary, Sarah Cadot, Gabriele Pizzolato, Julie Déchanet-Merville, Fréderic Martins, Loic Ysebaert, Fréderic Pont, Pierre Merville, Jean-Jacques FourniéDelphine Labourdette

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Abstract

γδ T lymphocytes represent ∼1% of human peripheral blood mononuclear cells and even more cells in most tissues of vertebrates. Although they have important anticancer functions, most current single-cell RNA sequencing (scRNA-seq) studies do not identify γδ T lymphocytes because their transcriptomes at the single-cell level are unknown. Here we show that high-resolution clustering of large scRNA-seq datasets and a combination of gene signatures allow the specific detection of human γδ T lymphocytes and identification of their T cell receptor (TCR)Vδ1 and TCRVδ2 subsets in large datasets from complex cell mixtures. In t-distributed stochastic neighbor embedding plots from blood and tumor samples, the few γδ T lymphocytes appear collectively embedded between cytotoxic CD8 T and NK cells. Their TCRVδ1 and TCRVδ2 subsets form close yet distinct subclusters, respectively neighboring NK and CD8 T cells because of expression of shared and distinct cytotoxic maturation genes. Similar pseudotime maturation trajectories of TCRVδ1 and TCRVδ2 γδ T lymphocytes were discovered, unveiling in both subsets an unattended pool of terminally differentiated effector memory cells with preserved proliferative capacity, a finding confirmed by in vitro proliferation assays. Overall, the single-cell transcriptomes of thousands of individual γδ T lymphocytes from different CMV+ and CMV- donors reflect cytotoxic maturation stages driven by the immunological history of donors. This landmark study establishes the rationale for identification, subtyping, and deep characterization of human γδ T lymphocytes in further scRNA-seq studies of complex tissues in physiological and disease conditions.
Lingua originaleEnglish
pagine (da-a)201818488-
Numero di pagine0
RivistaProceedings of the National Academy of Sciences of the United States of America
Stato di pubblicazionePublished - 2019

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Pizzolato, G., Dieli, F., Meraviglia, S., Franchini, D-M., Tosolini, M., Valle, C., Poupot, M., Laurent, C., Milpied, P., Kaminski, H., Martins, F., Quillet-Mary, A., Cadot, S., Pizzolato, G., Déchanet-Merville, J., Martins, F., Ysebaert, L., Pont, F., Merville, P., ... Labourdette, D. (2019). Single-cell RNA sequencing unveils the shared and the distinct cytotoxic hallmarks of human TCRVδ1 and TCRVδ2 γδ T lymphocytes. Proceedings of the National Academy of Sciences of the United States of America, 201818488-.