Autocrine IL-10 impairs dendritic cell (DC)-derived immune responses to mycobacterial infection by suppressing DC trafficking to draining lymph nodes and local IL-12 production.
The production of IL-12 by dendritic cells (DC) early in an immune response is considered critical for the polarization of CD4(+) T lymphocyte response towards a Th1 pattern, a key process in the clearance of intracellular pathogens. Infection of bone marrow-derived DC with Mycobacterium bovis Bacillus Calmette Guérin (BCG) induced a concurrent and dose-dependent releaseof IL-10 and IL-12. Here we examined whether the production of IL-10 by DC affected their IL-12 response to mycobacterial infection and the generation of protective immune responses in vivo. Compared to wild-type (WT) DC, DC deficient for IL-10 synthesis (IL-10(-/-)) showed increased IL-12 production in response to BCG infection and CD40 stimuli in vitro. Moreover, when transferred into mice, infected IL-10(-/-) DC were more efficient than WT DC at inducing IFN-gamma production to mycobacterial antigens in the draining lymph nodes (DLN). This effect was associated with increased trafficking of IL-10(-/-) DC to the DLN and enhanced IL-12 production by DC within the DLN. These data show that autocrine IL-10 exerts a dual inhibitory effect on the induction of primary immune responses by DC: first, by down-regulating the migration of infected DC to the DLN and second, by modulating the IL-12 production by DC in the DLN.
Demangel
Caroline
C
Centenary Institute of Cancer Medicine and Cell Biology, Newtown, NSW, Australia.
Bertolino
Patrick
P
Britton
Warwick J
WJ
D000818:Animals; D019898:Autocrine Communication; D019013:CD40 Antigens / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D016753:Interleukin-10 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018664:Interleukin-12 / Q000096:biosynthesis* / Q000235:genetics; D008198:Lymph Nodes / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009163:Mycobacterium bovis / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D014376:Tuberculosis / Q000276:immunology* / Q000382:microbiology
D019013:CD40 Antigens; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma