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

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.

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/CREBlimp-1^flox/flox mice, which exhibit abrogated T_RM cell formation, whereafter the mice were fed a Western-type diet for 10 weeks.

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.

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.