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.

• MeSH
• Biomarkers MeSH
• Cell Differentiation immunology   MeSH
• CD8-Positive T-Lymphocytes immunology   metabolism   MeSH
• Telomere Homeostasis MeSH
• Immunophenotyping MeSH
• Immunologic Memory * MeSH
• Humans MeSH
• Lymphoid Progenitor Cells cytology   immunology   metabolism   MeSH
• Mice MeSH
• Gene Expression Profiling MeSH
• T-Lymphocyte Subsets immunology   metabolism   MeSH
• Computational Biology methods   MeSH
• High-Throughput Nucleotide Sequencing MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH