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

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.

Citation

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 Gattinoni, Shannon 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. Two subsets of stem-like CD8+ memory T cell progenitors with distinct fate commitments in humans. Nature immunology. 2020 Dec;21(12):1552-1562

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PMID: 33046887

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