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

Giovanni Galletti, Gabriele De Simone, Emilia M.C. Mazza, Simone Puccio, Claudia Mezzanotte, Timothy M. Bi, Alexey N. Davydov, Maria Metsger, Eloise Scamardella, Giorgia Alvisi, Federica De Paoli, Veronica Zanon, Alice Scarpa, Barbara Camisa, Federico S. Colombo, Achille Anselmo, Clelia Peano, Sara Polletti, Domenico Mavilio, Luca GattinoniShannon K. Boi, Benjamin A. Youngblood, Rhiannon E. Jones, Duncan M. Baird, Emma Gostick, Sian Llewellyn-Lacey, Kristin Ladell, David A. Price, Dmitriy M. Chudakov, Evan W. Newell, Monica Casucci, Enrico Lugli

Research output: Contribution to journalArticlepeer-review

66 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1552-1562
Number of pages11
JournalNature Immunology
Issue number12
Publication statusPublished - Dec 2020


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