CCR9 signaling in dendritic cells drives the differentiation of Foxp3⁺ Tregs and suppresses the allergic IgE response in the gut

Abstract

The chemokine receptor CCR9 and its only known ligand CCL25 play an important role in gut inflammation and autoimmune colitis. The function of CCR9‐CCL25 in the migration of immune cells is well characterized. However, its role in the immune cell differentiation is mostly not known. Using dextran sodium sulfate (DSS)‐induced gut inflammation model, we showed that CCR9+ dendritic cells (DCs) specifically CD11b−CD103+ DCs were significantly increased in the gut‐associated lymphoid tissues (GALT) compared to control mice. These CCR9+ DCs express lower MHC II and CD86 molecules and had regulatory surface markers (FasL and latency‐associated peptide, LAP) in the GALT. In the presence of CCL25, CCR9+ DCs promoted in vitro differentiation of Foxp3+ regulatory CD4+ T cells (Tregs). CCL25‐induced differentiation of Tregs was due to intrinsic signaling in the DCs but not through CD4+ T cells, which was driven by the production of thymic stromal lymphopoietin (TSLP) and not IL‐10. Furthermore, adoptive transfer of CCR9+ DCs in C57BL/6 mice promoted Tregs but reduced the Th17 cells in the GALT, and also suppressed the OVA‐specific gut‐allergic response. Our results suggest CCR9+ DCs have a regulatory function and may provide a new cellular therapeutic strategy to control gut inflammation and allergic immune reaction.

The Regulatory Function of CCR9+ Dendritic Cells in Inflammation and Autoimmunity

“…CCL8 is also a ligand for CCR1 and CCR5 and involved in the migration of pDCs and cDCs in the thymus ( 40 ). Our recent study also suggests that CD103 + DCs and thymic DCs are a potent inducer of Treg in the presence of CCL25 ( 14 ). Thus, chemokine receptors play an important role in the thymic settling of DCs and controlling the central tolerance.…”

“…However, during inflammation, DCs promote the generation of Th1/Th17 by secreting proinflammatory cytokines ( 23 ). CCR9 controls the migration of CD11c + DCs into the gut ( 14 , 24 ) and also drives the recruitment of various subsets of DCs into the PP and mLN during inflammation ( 14 ). PP with specialized M cells uptake and recognize particulate antigens in a controlled manner and induce tolerance during homeostasis ( 25 , 26 ).…”

“…CD103 + DCs play a protective role at the initial phase of inflammation, whereas in the chronic phase, CD11b + DCs show a pathogenic role by inducing Th1/Th17 response ( 28 , 29 ). Our recent study demonstrates that CCR9 is expressed in various subsets of DCs during homeostatic and gut inflammation ( 14 ). Inflammation increases CCR9 expression on CD103 + CD11b - , CD103 - CD11b + , and CD103 + CD11b + subset in PP and mLN ( 14 ).…”

“…Our recent study demonstrates that CCR9 is expressed in various subsets of DCs during homeostatic and gut inflammation ( 14 ). Inflammation increases CCR9 expression on CD103 + CD11b - , CD103 - CD11b + , and CD103 + CD11b + subset in PP and mLN ( 14 ). Thus, CCR9 affects the distribution of a different subset of cDCs in the gut during homeostasis and inflammation ( Figure 1 ).…”

“…Furthermore, these intestinal pDCs help in the rapid mobilization of myeloid DCs into LP ( 8 ). In addition to distribution, CCR9 affects the function of DCs during inflammation ( 14 , 24 ). Previous work has shown that CCR9 + pDCs inhibit T cell proliferation and induce Foxp3 + regulatory T cells ( 7 ).…”