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, the cell-intrinsic role of Ahr in CD8+ T cells, remains elusive. Herein we show that Ahr acts as a promoter of resident memory CD8+ T cell (TRM) differentiation and function. Under steady state conditions or in an oral infection model, genetic ablation of Ahr in CD8+ T cells leads to an increase in CD127–KLRG1+ short lived effector cells (TSLE) and CD44+CD62L+ T central memory (TCM) cells, but a reduction in Granzyme B-producing CD69+CD103+ T resident memory (TRM) cells. Genome-wide transcriptome and cistrome analyses reveal that Ahr suppresses the circulating while promoting the resident memory core gene program. A tumor resident polyfunctional CD8+ T cell population dependent on Ahr is revealed by single cell RNA-Seq, and deletion of Ahr in CD8+ T cells compromises anti-tumor immunity. Consistent with mouse, human IEL CD8+ T cells highly express AHR that regulates in vitro TRM differentiation and Granzyme B production. Collectively, these data suggest that Ahr is an important cell-intrinsic factor for CD8+ T cell immunity. RNA-seq (2 replicates) analysis of CD8+ T cells isolated from small intestine IEL of Ahrf/fCd8cre (Ahr_CD8cre) mice vs Ahrf/f (CTRL) mice, RNA-seq (2 replicates) analysis of Ahr+/+ vs Ahr –/– antigen specific (OTI) CD8+ T cells isolated from the small intestine IEL of CD45.1/1 mice on day 9 post L.m.-OVA infection, ChIP-seq analysis of CD8+ T cells isolated from spleen of Ahr+/+ vs Ahr –/– mice and cultured in vitro under TRM-like skewing conditions, scRNA-seq (2 replicates) analysis of CD45+ cells isolated from B16F10 tumors from Ahr+/+ vs Ahr –/– mice.