The aryl hydrocarbon receptor cell intrinsically promotes resident memory CD8⁺ T cell differentiation and function

The Aryl hydrocarbon receptor (Ahr) regulates the differentiation and function of CD4⁺ T cells; however, its cell-intrinsic role in CD8⁺ T cells remains elusive. Herein we show that Ahr acts as a promoter of resident memory CD8⁺ T cell (T_RM) differentiation and function. Genetic ablation of Ahr in mouse CD8⁺ T cells leads to increased CD127^-KLRG1⁺ short-lived effector cells and CD44⁺CD62L⁺ T central memory cells but reduced granzyme-B-producing CD69⁺CD103⁺ T_RM cells. Genome-wide analyses reveal that Ahr suppresses the circulating while promoting the resident memory core gene program. A tumor resident polyfunctional CD8⁺ T cell population, revealed by single-cell RNA-seq, is diminished upon Ahr deletion, compromising anti-tumor immunity. Human intestinal intraepithelial CD8⁺ T cells also highly express AHR that regulates in vitro T_RM differentiation and granzyme B production. Collectively, these data suggest that Ahr is an important cell-intrinsic factor for CD8⁺ T cell immunity.