CCL25 mediates the localization of recently activated CD8αβ+ lymphocytes to the small-intestinal mucosa

The intestinal mucosa is continually exposed to a large array of foreign antigens and must respond appropriately to maintain mucosal integrity while at the same time mounting effective immune responses to potential pathogens. The recruitment of T lymphocytes to intestinal effector sites is thought to play a critical role in this process. Following activation in secondary lymphoid organs, T lymphocytes gain the ability to migrate from the blood to tertiary effector tissues such as the intestine and skin (1). Subsets of previously activated T lymphocytes display selective tissue tropism for these sites, a process that is controlled by specific combinations of cell adhesion molecules (1, 2). Previously activated T lymphocytes homing to the intestine express high levels of α4β7 integrin, whose ligand, MAdCAM-1, is expressed on postcapillary venules in the intestinal lamina propria. Indeed, β7 integrin appears to be critical for the entry of previously activated T lymphocytes into the intestinal lamina propria and epithelium (3, 4). In addition to cell adhesion molecules, accumulating evidence exists for an involvement of chemokines and their receptors in the recruitment of activated lymphocyte subsets to effector tissues (5). For example, the CC chemokine receptor 4 (CCR4) and the CCR10 ligand, CCL27, were recently shown to contribute to lymphocyte recruitment to inflamed skin (6, 7). The chemokine receptor CCR9 is selectively and functionally expressed on human small-intestinal lymphocytes (8), and its ligand, CCL25, is constitutively expressed by murine and human small-intestinal epithelial cells (9, 10), indicating a potential role for this chemokine receptor/chemokine pair in lymphocyte localization to the small intestine. However, examination of CD8αβ+ lymphocyte numbers in the small-intestinal epithelium of CCR9–/– mice has yielded conflicting results (11, 12). Furthermore, smallintestinal epithelial cells constitutively express a number of chemokines with activity for T lymphocytes, including CXCL12, CCL28, and CX3CL1, indicating a potential role for other chemokines in this process (13–15). Thus the in vivo role of CCL25 and CCR9 in T lymphocyte recruitment to the small intestine remains unclear. In the current study we have examined expression and regulation of CCR9 on murine CD8αβ+ lymphocytes in vivo and determined the role of CCL25 in the recruitment of recently activated CD8αβ+ lymphocytes to the small-intestinal mucosa.