Interleukin 23 production by intestinal CD103(+)CD11b(+) dendritic cells in response to bacterial flagellin enhances mucosal innate immune defense.
Microbial penetration of the intestinal epithelial barrier triggers inflammatory responses that include induction of the bactericidal C-type lectin RegIIIγ. Systemic administration of flagellin, a bacterial protein that stimulates Toll-like receptor 5 (TLR5), induces epithelial expression of RegIIIγ and protects mice from intestinal colonization with antibiotic-resistant bacteria. Flagellin-induced RegIIIγ expression is IL-22 dependent, but how TLR signaling leads to IL-22 expression is incompletely defined. By using conditional depletion of lamina propria dendritic cell (LPDC) subsets, we demonstrated that CD103(+)CD11b(+) LPDCs, but not monocyte-derived CD103(-)CD11b(+) LPDCs, expressed high amounts of IL-23 after bacterial flagellin administration and drove IL-22-dependent RegIIIγ production. Maximal expression of IL-23 subunits IL-23p19 and IL-12p40 occurred within 60 min of exposure to flagellin. IL-23 subsequently induced a burst of IL-22 followed by sustained RegIIIγ expression. Thus, CD103(+)CD11b(+) LPDCs, in addition to promoting long-term tolerance to ingested antigens, also rapidly produce IL-23 in response to detection of flagellin in the lamina propria.
Infectious Diseases Service, Department of Medicine, Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Melissa A
MA
Kinnebrew
Charlie G
CG
Buffie
Gretchen E
GE
Diehl
Lauren A
LA
Zenewicz
Ingrid
I
Leiner
Tobias M
TM
Hohl
Richard A
RA
Flavell
Dan R
DR
Littman
Eric G
EG
Pamer
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D039481:CD11b Antigen / Q000378:metabolism; D003713:Dendritic Cells / Q000145:classification / Q000276:immunology*; D005408:Flagellin / Q000008:administration & dosage / Q000276:immunology*; D007113:Immunity, Innate; D018928:Immunity, Mucosal; D039001:Integrin alpha Chains / Q000378:metabolism; D053759:Interleukin-23 / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D007378:Interleukins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D007413:Intestinal Mucosa / Q000276:immunology* / Q000382:microbiology*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000073718:Pancreatitis-Associated Proteins; D011506:Proteins / Q000235:genetics; D015398:Signal Transduction / Q000276:immunology; D051198:Toll-Like Receptor 5 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D000097043:Interleukin-22
D015703:Antigens, CD; D039481:CD11b Antigen; D005408:Flagellin; D039001:Integrin alpha Chains; D053759:Interleukin-23; D007378:Interleukins; D008565:Membrane Proteins; D000073718:Pancreatitis-Associated Proteins; D011506:Proteins; D051198:Toll-Like Receptor 5; D000097043:Interleukin-22; C490255:Reg3g protein, mouse; C091367:alpha E integrins; C084881:flt3 ligand protein