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.