CD4 ؉ T-cell entry to the intestinal mucosa is central to the generation of mucosal immunity as well as chronic intestinal inflammation, yet the mechanisms regulating this process remain poorly defined. Here we show that murine small intestinal CD4 ؉ lamina propria lymphocytes express a heterogeneous but restricted array of chemokine receptors including CCR5, CCR6, CCR9, CXCR3, and CXCR6. CD4 ؉ T-cell receptor transgenic OT-II cells activated in mesenteric lymph nodes acquired a distinct chemokine receptor profile, including expression of CCR6, CCR9, and CXCR3 that was only partially reproduced in vitro after priming with mesenteric lymph node dendritic cells. A subset of these effector CD4 ؉ T cells, expressing CD69 and ␣ 4 ␤ 7 , entered the intestinal lamina propria and the majority of these cells expressed CCR9. CCR9 ؊/؊ OT-II cells were disadvantaged in their ability to localize to the intestinal lamina propria; however, they were readily detected at this site and expressed ␣ 4 ␤ 7 , but little CCR2, CCR5, CCR6, CCR8, CCR10, CXCR3, or CXCR6. Thus, whereas CD4 ؉ T cells activated in gut-associated lymphoid tissue express a restricted chemokine receptor profile, including CCR9, targeting both CCR9-dependent and CCR9-independent entry mechanisms is likely to be important to maximally inhibit accumulation of these cells within the small intestinal mucosa. IntroductionThe intestinal lamina propria (LP) contains a large number of previously activated/memory CD4 ϩ T cells that play a central role in intestinal immunity and in the induction and maintenance of chronic intestinal inflammation. 1 T-cell entry into the intestinal mucosa is mediated by distinct sets of cell adhesion molecules expressed on the T cell and intestinal microvascular endothelial surface. Interaction between the gut-associated integrin ␣ 4 ␤ 7 , on the T-cell surface, with its ligand mucosal addresin cell adhesion molecule 1 (MAdCAM-1) on intestinal microvascular endothelium cells is important for T-cell entry into the LP. [2][3][4][5] In addition, antibody neutralization studies have suggested a role for P-selectin and P-selectin glycoprotein ligand 1 (PSGL-1) in effector CD4 ϩ T-cell entry to this site. 5 T-cell entry into nonlymphoid tissues is also regulated by chemokine/chemokine receptors and the chemokine receptor CCR9 is required for efficient effector CD8 ϩ T-cell localization to the small intestinal epithelium. 6,7 However, since CCR9 Ϫ/Ϫ mice have normal numbers of LP T cells, 8,9 the particular role of CCR9 or additional chemokine receptors in CD4 ϩ T-cell localization to the intestinal LP remains unclear.The ability of T cells to enter nonlymphoid effector tissues is acquired following T-cell priming in secondary lymphoid organs and is mediated, in part, through the de novo expression of chemokine receptors. 10,11 In vitro, the chemokine receptor profile induced following CD4 ϩ T-cell priming is highly dependent on the culture conditions and the nature of antigenpresenting cells. [12][13][14] In vivo, distinct subsets of B-helper ...