Identification of a chemokine network that recruits FoxP3(+) regulatory T cells into chronically inflamed intestine.
OBJECTIVE
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.
Kang
Seung G
SG
Laboratory of Immunology and Hematopoiesis, Department of Comparative Pathobiology, Purdue Cancer Center, Purdue University Life Science Program, Purdue University, West Lafayette, Indiana 47907, USA.
Piniecki
Ronald J
RJ
Hogenesch
Harm
H
Lim
Hyung W
HW
Wiebke
Eric
E
Braun
Stephen E
SE
Matsumoto
Satoshi
S
Kim
Chang H
CH
D000577:Amides / Q000494:pharmacology; D000818:Animals; D065100:CCR5 Receptor Antagonists; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D018946:Chemokine CCL5; D018925:Chemokines / Q000096:biosynthesis*; D019742:Chemokines, CC / Q000096:biosynthesis; D019743:Chemokines, CXC / Q000096:biosynthesis; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D002908:Chronic Disease; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D007079:Ileitis / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008213:Lymphocyte Activation; D051379:Mice; D008806:Mice, Inbred AKR; D016513:Mice, SCID; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D019713:Receptors, CCR5 / Q000096:biosynthesis; D012720:Severity of Illness Index; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism*; D013997:Time Factors; D015854:Up-Regulation
D000577:Amides; D065100:CCR5 Receptor Antagonists; C503460:Ccl5 protein, mouse; D018946:Chemokine CCL5; D018925:Chemokines; D019742:Chemokines, CC; D019743:Chemokines, CXC; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D000644:Quaternary Ammonium Compounds; D019713:Receptors, CCR5; C119369:TAK 779