Pivotal role of CCL25 (TECK)-CCR9 in the formation of gut cryptopatches and consequent appearance of intestinal intraepithelial T lymphocytes

Abstract

Cryptopatches (CP) are murine gut anatomical sites for generating thymus‐independent intraepithelial T lymphocytes (IEL). However, it remains elusive how lympho‐hematopoietic progenitor cells migrate from bone marrow (BM) into CP and differentiate into IEL. Here we show that mice reconstituted with BM‐derived c‐kit⁺ cells express CCL25 (TECK)‐intrakine gene, which reduces specifically the chemotactic response to CCL25 but not CXCL12 in the thymocytes. These mice exhibited a dramatic reduction of CP and IEL in the small intestine, and harbored conspicuously decreased numbers of c‐kit⁺ cells in the emaciated CP. In contrast, T cells in the thymic, splenic and lymph node compartments developed normally in these mice. Importantly, it was demonstrated that CD11c⁺ dendritic stromal cells in CP expressed CCL25 and c‐kit⁺ Lin^– BM cells displayed vigorous chemotactic response to CCL25. Furthermore, RT‐PCR analysis detects mRNA expression of CCR9 in the c‐kit⁺ Lin^– BM cells. Thus, these results demonstrate that the CCL25–CCR9 pathway is essential for CP formation and the consequent appearance of IEL.