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Two subsets of stem-like CD8+ memory T cell progenitors with distinct fate commitments in humans

Nature Immunology volume 21, pages 1552–1562 (2020)Cite this article

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Abstract

T cell memory relies on the generation of antigen-specific progenitors with stem-like properties. However, the identity of these progenitors has remained unclear, precluding a full understanding of the differentiation trajectories that underpin the heterogeneity of antigen-experienced T cells. We used a systematic approach guided by single-cell RNA-sequencing data to map the organizational structure of the human CD8+ memory T cell pool under physiological conditions. We identified two previously unrecognized subsets of clonally, epigenetically, functionally, phenotypically and transcriptionally distinct stem-like CD8+ memory T cells. Progenitors lacking the inhibitory receptors programmed death-1 (PD-1) and T cell immunoreceptor with Ig and ITIM domains (TIGIT) were committed to a functional lineage, whereas progenitors expressing PD-1 and TIGIT were committed to a dysfunctional, exhausted-like lineage. Collectively, these data reveal the existence of parallel differentiation programs in the human CD8+ memory T cell pool, with potentially broad implications for the development of immunotherapies and vaccines.

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Fig. 1: Heterogeneity of the human CD8+ memory T cell pool.
Fig. 2: Identification of stem-like CD8+ memory T cell progenitors with differential expression of GZMK, PD-1 and TIGIT.
Fig. 3: Functional properties of TSTEM and TPEX cells.
Fig. 4: Fate commitments of TSTEM and TPEX cells.
Fig. 5: Antigen specificity and clonal identity of TSTEM and TPEX cells.

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Data availability

Publicly available scRNA-seq data were retrieved from the Gene Expression Omnibus via accession code GSE120575. Microarray data from YFV-17D-specific CD8+ T cells were retrieved from the Gene Expression Omnibus via accession code GSE26347. Gene sets of interest were retrieved from the Molecular Signatures Database (http://www.broadinstitute.org/gsea/msigdb/index.jsp). The ATAC-seq data reported in this paper are available on request. The bulk RNA-seq and scRNA-seq data reported in this paper have been deposited in the Gene Expression Omnibus under accession code GSE147398. The TCR-seq data reported in this paper have been deposited at the European Bioinformatic Institute under accession code E-MTAB-8892. All other data that support the findings of this study are available on request from the corresponding author.

Code availability

Scripts used to analyze the ATAC-seq data are available at https://github.com/luglilab/SP018_CD8_Galletti_et_al. All other codes are available on request.

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Acknowledgements

The authors thank G. Natoli (European Institute of Oncology, Milan) for assistance with the ATAC-seq protocol, R. Roychoudhuri (University of Cambridge) and M. Iannacone (San Raffaele Scientific Institute, Milan) for critical discussions, and G. Cugini and G. Colombo (Humanitas Clinical and Research Center, Milan) for the provision of lymph node samples. This work was funded by the European Research Council (ERC-2014-STG PERSYST no. 640511 to E.L.) and by the Associazione Italiana per la Ricerca sul Cancro (AIRC IG 20676 to E.L.). Additional support was provided by the Associazione Italiana per la Ricerca sul Cancro (AIRC IG 21567 to D.M.), the Italian Ministry of Health (Bando Ricerca Finalizzata PE-2016-02363915 to D.M.), the Intramural Research Fund of the Humanitas Clinical and Research Center (5 ×1000 2019 Program to D.M.) and Cancer Research UK (C17199/A18246/A29202 to D.M.B.). G.G., G.D.S., S.P. and E.S. were supported by Fellowships from the Fondazione Italiana per la Ricerca sul Cancro-Associazione Italiana per la Ricerca sul Cancro (FIRC-AIRC). A.N.D. and M.M. were supported by the Ministry of Education, Youth, and Sports of the Czech Republic (CEITEC 2020 LQ1601). D.A.P. was supported by a Wellcome Trust Senior Investigator Award (100326/Z/12/Z). D.M.C. was supported by the Ministry of Health of the Russian Federation (0908300057056). The purchase of a FACSSymphony A5 was defrayed in part by a grant from the Italian Ministry of Health (Agreement 82/2015).

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Author notes

  1. These authors contributed equally: Giovanni Galletti, Gabriele De Simone, Emilia M. C. Mazza.

Authors and Affiliations

  1. Laboratory of Translational Immunology, Humanitas Clinical and Research Center – IRCCS, Rozzano, Milan, Italy

    Giovanni Galletti, Gabriele De Simone, Emilia M. C. Mazza, Simone Puccio, Eloise Scamardella, Giorgia Alvisi, Federica De Paoli, Veronica Zanon, Alice Scarpa & Enrico Lugli

  2. Innovative Immunotherapies Unit, Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy

    Claudia Mezzanotte, Barbara Camisa & Monica Casucci

  3. Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    Timothy M. Bi & Evan W. Newell

  4. Central European Institute of Technology, Brno, Czech Republic

    Alexey N. Davydov & Maria Metsger

  5. Humanitas Flow Cytometry Core, Humanitas Clinical and Research Center – IRCCS, Rozzano, Milan, Italy

    Federico S. Colombo, Achille Anselmo & Enrico Lugli

  6. Institute of Genetic and Biomedical Research, UoS Milan, National Research Council, Rozzano, Milan, Italy

    Clelia Peano

  7. Genomic Unit, Humanitas Clinical and Research Center – IRCCS, Rozzano, Milan, Italy

    Clelia Peano

  8. Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy

    Sara Polletti

  9. Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center – IRCCS, Rozzano, Milan, Italy

    Domenico Mavilio

  10. Department of Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy

    Domenico Mavilio

  11. Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

    Luca Gattinoni

  12. Regensburg Center for Interventional Immunology, Regensburg, Germany

    Luca Gattinoni

  13. University of Regensburg, Regensburg, Germany

    Luca Gattinoni

  14. St. Jude Children’s Research Hospital, Memphis, TN, USA

    Shannon K. Boi & Benjamin A. Youngblood

  15. Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, UK

    Rhiannon E. Jones & Duncan M. Baird

  16. Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK

    Emma Gostick, Sian Llewellyn-Lacey, Kristin Ladell & David A. Price

  17. Systems Immunity Research Institute, Cardiff University School of Medicine, Cardiff, UK

    David A. Price

  18. Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia

    Dmitriy M. Chudakov

  19. Pirogov Russian National Research Medical University, Moscow, Russia

    Dmitriy M. Chudakov

  20. Center of Life Sciences, Skolkovo Institute of Science and Technology, Moscow, Russia

    Dmitriy M. Chudakov

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  1. Giovanni Galletti
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Contributions

G.G. and E.L. conceived the study; G.G., G.D.S., E.M.C.M., S.P., C.M., T.M.B., A.N.D., M.M., E.S., G.A., F.D.P., V.Z., A.S., B.C., F.S.C., A.A., C.P., S.P., L.G., R.E.J., D.M.B., E.G., S.L.-L. and K.L. performed experiments; G.G., G.D.S., E.M.C.M., S.P., T.M.B., A.N.D., D.M.B., D.M.C., E.W.N., M.C. and E.L. analyzed data; D.M., S.K.B., B.A.Y. and D.A.P. provided critical expertise and resources; E.L. supervised the study; G.G., D.A.P. and E.L. wrote the manuscript. All authors contributed intellectually and approved the manuscript.

Corresponding author

Correspondence to Enrico Lugli.

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Competing interests

The Laboratory of Translational Immunology receives reagents in kind as part of a collaborative research agreement with BD Biosciences (Italy). L.G. and E.L. are inventors on a patent describing methods for the generation and isolation of TSCM cells. E.L. has a consulting agreement with Achilles Therapeutics. L.G. has consulting agreements with Lyell Immunopharma and Advaxis Immunotherapies. E.W.N. is a cofounder and advisor for ImmunoScape. The other authors have no competing interests.

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Supplementary information

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Supplementary Figures 1–5.

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Supplementary Table 1

Samples used in this study.

Supplementary Table 2

Differentially expressed genes identified by scRNA-seq.

Supplementary Table 3

Differentially expressed genes between clusters C2 and C6 from scRNA-seq.

Supplementary Table 4

Differentially expressed genes from bulk RNA-seq plus enrichment analysis with publicly available data.

Supplementary Table 5

Differentially expressed genes between activated TSTEM and TPEX cells.

Supplementary Table 6

Flow cytometry reagents.

Supplementary Table 7

Mass cytometry reagents.

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Galletti, G., De Simone, G., Mazza, E.M.C. et al. Two subsets of stem-like CD8+ memory T cell progenitors with distinct fate commitments in humans. Nat Immunol 21, 1552–1562 (2020). https://doi.org/10.1038/s41590-020-0791-5

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