Lineage analysis defines subpopulations of human lung tissue-resident memory CD8+ T cells

Abstract

Abstract Tissue resident memory T cells (TRM) are important for local immunity and recall responses. In contrast to effector and central memory T cells, TRM remain in the tissues and do not circulate throughout the body. CD69 and CD103 expression are distinguishing markers of TRM cells, although TRM cells expressing only one marker, or absent of both markers, have been described, suggesting further heterogeneity beyond these markers. Many of the phenotypic characteristics and transcriptional properties of TRM cells have been defined in animal models, where in vivo labeling can be used to define tissue residency. Therefore, a deeper understanding of what defines human TRM cells and their molecular heterogeneity is necessary. To address this, single-cell multi-omics data of memory CD8+ T cells isolated from human lungs that have been phenotypically subsetted into CD69+, CD69+CD103+, CD69-CD103-, and naive cells were collected and analyzed by scATAC-seq and scRNA-seq approaches. A lineage analysis of these data identified multiple distinct lineages of TRM cells in human lungs. From this, we defined the genes that drive each lineage through their differentiation program, the variable transcription factor motifs that distinguish each lineage terminal state, and estimate the rate of differentiation as the cells transition. In identifying these subpopulations, we can begin to understand the heterogeneity of TRM cells in humans on a molecular level. Supported by a grant from the NIH/NIAID (75N93019R00028) and a grant from the NIH/NHLBI (R35 HL150803)