A Committed Tissue-Resident Memory T Cell Precursor Within the Circulating CD8+ Effector T Cell Pool

An increasing body of evidence emphasizes the role of tissue-resident memory T cells (T-RM) in the defense against recurring pathogens and malignant neoplasms. However, little is known with regard to the origin of these cells and their kinship to other CD8(+) T cell compartments. To address this issue, we followed the antigen-specific progeny of individual naive CD8(+) T cells to the T effector (T-EFF), T circulating memory (T-CIRCM), and T-RM pools by lineage-tracing and single-cell transcriptome analysis. We demonstrate that a subset of T cell clones possesses a heightened capacity to form T-RM, and that enriched expression of T-RM-fate-associated genes is already apparent in the circulating T-EFF offspring of such clones. In addition, we demonstrate that the capacity to generate T-RM is permanently imprinted at the clonal level, before skin entry. Collectively, these data provide compelling evidence for early stage T-RM fate decisions and the existence of committed T-RM precursor cells in the circulatory T-EFF compartment.