Endogenous antigen presenting cell-derived IL-10 inhibits T lymphocyte responses to commensal enteric bacteria.
Interleukin-10 deficient (IL-10-/-) mice develop chronic T cell-mediated colitis when colonized with normal commensal bacteria, but germ-free (GF) IL-10-/- mice remain disease-free. Antigen presenting cells (APC) secrete regulatory cytokines that help determine T lymphocyte activation or tolerance. CD4(+) T cells from the mesenteric lymph nodes of inflamed IL-10-/- mice secrete more IFN-gamma and IL-17 when cultured with cecal bacterial lysate-pulsed splenic APC from IL-10-/- mice than when cultured with normal control APC. GF IL-10-/- APC induce similar IFN-gamma and IL-17 responses; therefore, the functional difference between normal and IL-10 deficient APC is inherent to the lack of IL-10 and not secondary to inflammation. Bacterial lysate-pulsed normal APC cultured with CD4(+) cells from colitic IL-10-/- mice or with exogenous IFN-gamma secrete higher amounts of IL-10 compared to the same APC cultured with naïve T cells. APC enriched for CD11c(+) cells are potent activators of IFN-gamma and IL-17 production by CD4(+) cells from IL-10-/- mice. These APC also produce IL-12/IL-23 p40 and IL-10. Recombinant IL-10 suppressed and anti-IL-10 receptor antibody increased IFN-gamma, IL-17 and IL-12/IL-23 p40 production in bacterial lysate-pulsed APC and plus CD4(+) T cell co-cultures. Taken together, our results show that endogenous IL-10 produced by APC inhibits responses to commensal bacteria and influences the ability of APC to stimulate IFN-gamma-producing effector lymphocytes, which reciprocally, induce IL-10 production by APC. Cytokines produced by APC are an important determinant of pathogenic versus protective mucosal immune responses to colonic bacterial stimulation.
Albright
Carol A
CA
Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, USA.
Sartor
R Balfour
RB
Tonkonogy
Susan L
SL
D000818:Animals; D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000382:microbiology; D018920:Coculture Techniques; D003092:Colitis / Q000276:immunology* / Q000382:microbiology; D003106:Colon / Q000276:immunology* / Q000382:microbiology; D004755:Enterobacteriaceae / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D018664:Interleukin-12 / Q000096:biosynthesis / Q000276:immunology; D020381:Interleukin-17 / Q000096:biosynthesis / Q000276:immunology; D053759:Interleukin-23 / Q000096:biosynthesis / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout
D020381:Interleukin-17; D053759:Interleukin-23; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma