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.
Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, USA.
Carol A
CA
Albright
R Balfour
RB
Sartor
Susan L
SL
Tonkonogy
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