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

• Published in: Nature immunology Vol. 21; no. 12; pp. 1552 - 1562
• Main Authors: Galletti, Giovanni, De Simone, Gabriele, Mazza, Emilia M. C., Puccio, Simone, Mezzanotte, Claudia, Bi, Timothy M., Davydov, Alexey N., Metsger, Maria, Scamardella, Eloise, Alvisi, Giorgia, De Paoli, Federica, Zanon, Veronica, Scarpa, Alice, Camisa, Barbara, Colombo, Federico S., Anselmo, Achille, Peano, Clelia, Polletti, Sara, Mavilio, Domenico, Gattinoni, Luca, Boi, Shannon K., Youngblood, Benjamin A., Jones, Rhiannon E., Baird, Duncan M., Gostick, Emma, Llewellyn-Lacey, Sian, Ladell, Kristin, Price, David A., Chudakov, Dmitriy M., Newell, Evan W., Casucci, Monica, Lugli, Enrico
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.12.2020; Nature Publishing Group
• Subjects: 631/250/1619/554/1834; 631/250/2152/1566/1571; Animals; Antigens; Apoptosis; Biomarkers; Biomedical and Life Sciences; Biomedicine; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cell Differentiation - immunology; Computational Biology - methods; Gene Expression Profiling; Heterogeneity; High-Throughput Nucleotide Sequencing; Humans; Immunoglobulins; Immunologic Memory; Immunological memory; Immunology; Immunophenotyping; Immunoreceptor tyrosine-based inhibition motif; Immunotherapy; Infectious Diseases; Lymphocytes; Lymphocytes T; Lymphoid Progenitor Cells - cytology; Lymphoid Progenitor Cells - immunology; Lymphoid Progenitor Cells - metabolism; Memory cells; Mice; PD-1 protein; Progenitor cells; Ribonucleic acid; RNA; Stem cells; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; Telomere Homeostasis; Transcription
• ISSN: 1529-2908; 1529-2916
• DOI: 10.1038/s41590-020-0791-5

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. The identity of stem-cell memory progenitor cells has been unclear. Lugli and colleagues use high-dimensional approaches to identify two new progenitor populations of human T cells—one giving rise to a functional lineage, the other to an exhausted-like one.