CCR9+ dendritic cells promote the differentiation of Foxp3+ regulatory CD4 T cells

Abstract

Chemokine receptor CCR9 is known to play an important role in the migration of immune cells to the gut. Intestinal epithelial cells under gut inflammation or in inflammatory bowel disease (IBD) produce several folds higher CCL25, the only known ligand for CCR9, and drive the recruitment of CCR9+ immune cells. Due to its gut tropism activity, CCR9 and CCL25 are suggested as a potential therapeutic target. Still, many of the clinical trials targeting CCR9/CCL25 did not give a positive outcome; instead, they increase the severity of the disease. The non-chemotactic function of CCR9 in the gut inflammation and immunity is not known. Using dextran sodium sulfate (DSS)-induced gut inflammation model in C57BL/6 mice, we showed that CCR9+ DCs, specifically CD11b−CD103+ DCs recruited in high frequency to the gut and gut-associated lymphoid tissues (GALT) in DSS treated mice as compared to control group. These CCR9+ DCs showed lower MHC II and CD86 molecules and had higher regulatory surface markers (FasL and Latency-associated peptide, LAP) in the GALT. Further, we demonstrate that thymic stromal lymphopoietin (TSLP) produced by CCR9+ DCs but not IL-10 or TGF-β, promotes the differentiation of Foxp3+ Treg. Furthermore, adoptive transfer of CCR9+ DCs in C57BL/6 mice promoted Tregs but reduced the Th17 cells in the GALT, and also suppressed the ovalbumin-specific gut allergic immune response. Together, these results suggest that CCR9+ DCs have a regulatory function and can be explored as an adoptive cellular therapy to control the gut inflammation and allergic immune response.