Resident Memory T Cells in the Atherosclerotic Lesion Associate With Reduced Macrophage Content and Increased Lesion Stability

Abstract

BACKGROUND: Tissue resident memory T (T RM ) cells are a T-cell subset that resides at the site of prior antigen recognition to protect the body against reoccurring encounters. Besides their protective function, T RM cells have also been implicated in inflammatory disorders. T RM cells are characterized by the expression of CD69 and transcription factors Hobit (homolog of Blimp-1 [B lymphocyte–induced maturation protein 1] in T cells) and Blimp-1. As the majority of T cells in the arterial intima expresses CD69, T RM cells may contribute to the pathogenesis of atherosclerosis as well. Here, we aimed to assess the presence and potential role of T RM cells in atherosclerosis. METHODS: To identify T RM cells in human atherosclerotic lesions, a single-cell RNA-sequencing data set was interrogated, and T-cell phenotypes were compared with that of integrated predefined T RM cells. The presence and phenotype of T RM in atherosclerotic lesions was corroborated using a mouse model that enabled tracking of Hobit-expressing T RM cells. To explore the function of T RM cells during atherogenesis, RAG1 −/− (recombination activating gene 1 deficient) LDLr −/− (low-density lipoprotein receptor knockout) mice received a bone marrow transplant from Hobit KO/CRE Blimp-1 flox/flox mice, which exhibit abrogated T RM cell formation, whereafter the mice were fed a Western-type diet for 10 weeks. RESULTS: Human atherosclerotic lesions contained T cells that exhibited a T RM cell–associated gene signature. Moreover, a fraction of these T cells clustered together with predefined T RM cells upon integration. The presence of Hobit-expressing T RM cells in the atherosclerotic lesion was confirmed in mice. These lesion-derived T RM cells were characterized by the expression of CD69 and CD49α. Moreover, we demonstrated that this small T-cell subset significantly affects lesion composition, by reducing the amount of intralesional macrophages and increasing collagen content. CONCLUSIONS: T RM cells, characterized by the expression of CD69 and CD49α, constitute a minor population in atherosclerotic lesions and are associated with increased lesion stability in a Hobit and Blimp-1 knockout mouse model.