Identification of a Chemokine Network That Recruits FoxP3⁺ Regulatory T Cells Into Chronically Inflamed Intestine

Background & Aims: It has been unclear which chemokine network is involved in migration of T-cell subsets to chronically inflamed lesions of the intestine. SAMP1/YP mice develop a spontaneous chronic transmural intestinal lesion specifically in the ileum. Using these mice, we investigated the gut chemokine network involved in specific migration of T-cell subsets to the inflamed lesion of the intestine. Methods: We performed expression analyses of chemokines and their receptors, chemokine receptor blocking studies, and migration studies in vitro and in vivo to identify the gut chemokine network induced in intestinal inflammation and to determine its role in migration of conventional and FoxP3⁺ suppressor T cells to the inflamed intestine. Results: The expression of homeostatic chemokines was largely unchanged in the inflamed lesion of SAMP1/YP mice compared with control mice. However, an additional chemokine axis (CCL5-CCR5) was up-regulated in the inflamed intestine of SAMP1/YP mice compared with control mice. Activated T cells of SAMP1/YP mice compared with control mice were hyperresponsive to CCL5 in chemotaxis. CCR5⁺ T cells preferentially migrated to the inflamed lesion, which can be blocked by a CCR5 antagonist. Importantly, the FoxP3⁺ regulatory T cells of the inflamed lesion of SAMP1/YP mice highly expressed CCR5. CCR5 blockade suppressed the migration of FoxP3⁺ T cells into the inflamed intestine and significantly exacerbated the intestinal inflammation. Conclusions: The CCL5-CCR5 chemokine axis is involved in preferential recruitment of FoxP3⁺ regulatory T cells, which prevents further exacerbation of chronic inflammation in the intestine.

Abbreviations used in this paper: CFSE, 5-(and-6)-carboxyfluorescein diacetate succinimidyl ester, ELISA, enzyme-linked immunosorbent assay, IL, interleukin, MAdCAM-1, mucosal addressin cell adhesion molecule 1, MLN, mesenteric lymph node, PCR, polymerase chain reaction, SCID, severe combined immunodeficient, VCAM-1, vascular cell adhesion molecule 1