CCR9 INTRINSIC SIGNALING IN DENDRITIC CELLS PROMOTE THE DIFFERENTIATION OF FOXP3+ REGULATORY CD4 T CELLS IN THE GUT
- Girdhari Lal, India
Abstract
Background and Aims
The chemokine receptor CCR9 play important role in the migration of immune cells in the gut and shows a strong clinical association in inflammatory bowel disease (IBD). Several clinical trials were conducted by targeting CCR9 or its ligand CCL25 in IBD but failed. The detailed cellular and mechanism of CCR9 and CCL25 interactions and its effect various immune cells are not clearly understood.
Methods
Gut inflammation in C57BL/6 mice was induced by giving dextrans sodium sulfate (DSS; 2% w/v) in the drinking water. Dendritic cells (DC) subsets and CD4 T cells were characterized using flow cytometry. Naive CD4+CD25-CD44- T cells were in vitro differentiated into Th17 and Treg cells in the presence of CCR9+ or CCR9- DCs and recombinant CCL25.
Results
DSS treatment significantly increased the infiltration of CCR9+DCs in the gut-associated lymphoid tissues (GALT) compared to control mice. Among the CCR9+CD11c+DCs, the frequency of CD11b-CD103+ DCs was significantly higher in the GALT. CCR9+ DCs showed lower expression of MHC II and CD86 molecules, and higher FasL and latency associated peptides in the GALT. CCR9+DCs in the presence of purified recombinant CCL25 promoted the differentiation of Foxp3+ regulatory CD4 T cells in the culture. The differentiation of Foxp3+Tregs was due to thymic stromal lymphopoietin (TSLP) produced by DCs in the culture. Furthermore, the adoptive transfer of CCR9+DCs in C57BL6 mice suppresses the ova-specific gut allergic response.
Conclusions
Our data showed that CCR9+DCs have a regulatory function and may be exploited as a cellular therapy to control gut inflammation and autoimmunity.