Differential homing mechanisms regulate regionalized effector CD8αβ⁺ T cell accumulation within the small intestine

The CC chemokine receptor (CCR)9 is expressed on the majority of small intestinal, but few colonic, T cells, whereas its ligand CCL25 is constitutively expressed by small intestinal epithelial cells. As such, CCR9/CCL25 have been proposed to play a central role in regulating small intestinal but not colonic immune responses and thus to organize regionalized immunity within the intestinal mucosa. Here, we demonstrate that CCL25 is expressed at reduced levels by epithelial cells in the distal compared with proximal small intestine, which correlated with less efficient CCR9-dependent effector CD8αβ⁺ T cell entry into the ileal epithelium. In vitro-generated α₄β₇⁺ effector CD8αβ⁺ T cell entry into the lamina propria was less dependent on CCR9 than entry into the epithelium along the entire length of the small intestine and in particular in the ileum. CCR9-independent α₄β₇⁺ effector CD8αβ⁺ T cell entry was pertussis toxin-sensitive, suggesting a role for additional GαI-linked G protein-coupled receptors. Finally, in vivo-primed effector CD8αβ⁺ T cells displayed regionalized differences in their entry to the small intestinal epithelium with enhanced CCR9-independent entry to the ileum. These results highlight a hitherto underappreciated compartmentalization of immune responses within the small intestine and have direct implications for targeting strategies aimed at regulating T cell localization to the small intestinal mucosa.