Identification of T-RM subsets with distinct cellular states and memory potential

Abstract The memory CD8+ T cell population consists of distinct subsets that collaborate to provide robust immunological protection. Within the circulation, two broad classes exist – the shorter-lived effector and effector memory (TEM) cells with heightened effector function for immediate protection and the longer-lived central memory (TCM) cells with stem-like qualities and increased proliferation potential. Tissue-resident memory (TRM) cells are the prominent cell type permanently residing in non-lymphoid tissues acting as sentinels against reinfection. Despite the critical importance of the TRM subset, the extent of their phenotypic and functional heterogeneity remains unknown. Using single-cell gene expression analyses, we assessed small intestine intraepithelial TRM cells over the course of acute infection. Distinct subsets were identified and distinguished by reciprocal expression of effector- and memory-associated transcriptional regulators, Blimp1 and Id3, respectively. While the Blimp1hi subset was prominent at early time points, the Id3hi population persisted and was more abundant over time. Importantly, examination of the subset-specific transcriptional profiles revealed considerable enrichment for the effector/effector-memory gene signature within the Blimp1hiTRM subset and the central-memory gene signature within the Id3hi TRM population. Furthermore, Id3hi TRM cells exhibited more stem-like characteristics including increased capacity to proliferate following rechallenge. Taken together, this study reveals that similar to circulating memory, the TRM population is heterogeneous, comprising cells with contrasting differentiation states and memory potential.