Two subsets of stem-like CD8 + memory T cell progenitors with distinct fate commitments in humans
Giovanni Galletti1, Gabriele De Simone1, Emilia M C Mazza1, Simone Puccio1, Claudia Mezzanotte2, Timothy M Bi3, Alexey N Davydov4, Maria Metsger4, Eloise Scamardella1, Giorgia Alvisi1, Federica De Paoli1, Veronica Zanon1, Alice Scarpa1, Barbara Camisa2, Federico S Colombo5, Achille Anselmo5, Clelia Peano6,7, Sara Polletti8, Domenico Mavilio9,10, Luca Gattinoni11,12,13, Shannon K Boi14, Benjamin A Youngblood14, Rhiannon E Jones15, Duncan M Baird15, Emma Gostick16, Sian Llewellyn-Lacey16, Kristin Ladell16, David A Price16,17, Dmitriy M Chudakov18,19,20, Evan W Newell3, Monica Casucci2, Enrico Lugli21,22
- Laboratory of Translational Immunology, Humanitas Clinical and Research Center - IRCCS, Rozzano, Milan, Italy.
- Innovative Immunotherapies Unit, Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy.
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
- Central European Institute of Technology, Brno, Czech Republic.
- Humanitas Flow Cytometry Core, Humanitas Clinical and Research Center - IRCCS, Rozzano, Milan, Italy.
- Institute of Genetic and Biomedical Research, UoS Milan, National Research Council, Rozzano, Milan, Italy.
- Genomic Unit, Humanitas Clinical and Research Center - IRCCS, Rozzano, Milan, Italy.
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy.
- Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center - IRCCS, Rozzano, Milan, Italy.
- Department of Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy.
- Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
- Regensburg Center for Interventional Immunology, Regensburg, Germany.
- University of Regensburg, Regensburg, Germany.
- St. Jude Children's Research Hospital, Memphis, TN, USA.
- Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, UK.
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK.
- Systems Immunity Research Institute, Cardiff University School of Medicine, Cardiff, UK.
- Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia.
- Pirogov Russian National Research Medical University, Moscow, Russia.
- Center of Life Sciences, Skolkovo Institute of Science and Technology, Moscow, Russia.
- Laboratory of Translational Immunology, Humanitas Clinical and Research Center - IRCCS, Rozzano, Milan, Italy. enrico.lugli@humanitasresearch.it.
- Humanitas Flow Cytometry Core, Humanitas Clinical and Research Center - IRCCS, Rozzano, Milan, Italy. enrico.lugli@humanitasresearch.it.
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.
Presented By Giovanni Galletti | ORCID iD