Chemokine receptors play an important role in the recruitment of activated T cells to inflammatory sites. The aim of this study was to analyze the expression of the chemokine receptor CXCR3 on T lymphocytes in intestinal lymphoid tissues and to document the altered disposition of these cells in patients with inflammatory bowel disease (IBD). The expression and regulation of CXCR3 on mucosal lymphoid tissue and peripheral blood lymphocytes (PBLs) were analyzed by flow cytometry and Northern blotting. The migration of lamina propria lymphocytes (LPLs) and PBLs to interferon (IFN)-gamma-inducible protein (IP)-10 (or CXCL10) was evaluated by chemotaxis assays. IFN-gamma and interleukin-4-producing T lymphocytes were quantitated by intracellular staining, and IFN-gamma was measured in culture supernatants by enzyme-linked immunosorbent assay. CXCR3 is expressed on the majority of CD4 lamina propria (LP) T cells and correlates with a T-helper (Th) type 1/Th-0 cytokine phenotype on LP and mesenteric lymph node (MLN) CD4 T lymphocytes. IP-10/CXCL10 is more chemotactic in vitro for both CD4 and CD8 T cells that have been isolated from the LP compared with peripheral blood. CXCR3 protein, but not messenger RNA, expression was lower in inflamed LPLs compared with uninvolved LPLs in patients with ulcerative colitis but not in those with Crohn's disease. However, CXCR3 was expressed on a higher percentage of MLN CD4 T cells isolated from inflamed intestinal tissue, and CXCR3 expression could be induced in vitro with T-cell activation in MLN CD4 T cells. In summary, most CXCR3 T lymphocytes in normal intestinal tissues are Th-1/Th-0 effector/memory cells. Activation-dependent receptor regulation and alteration in receptor-bearing cells, primarily in MLN draining inflamed intestinal tissue, suggest an important role for this T-cell subset in the pathogenesis of human IBD.