Mice that are deficient in interleukin (IL)-10 develop colitis, mediated by T-helper (Th)1 and Th17 cells, and IL-10–producing regulatory T (Treg) cells suppress colitis, implicating IL-10 in maintaining mucosal homeostasis. We assessed the relative importance of immunoregulatory IL-10 derived from T cells or from antigen presenting cells (APCs) in development of intestinal inflammation.

CD4⁺ cells from germ-free (GF) or specific pathogen-free (SPF) IL-10^−/− or wild-type mice were injected into IL-10^−/−, Rag2^−/− mice or Rag2^−/− mice that express IL-10. After 6–8 weeks, we evaluated inflammation, spontaneous secretion of cytokines from colonic tissue, and mRNA levels of the transcription factor T-bet and the immunoregulatory cytokine transforming growth factor (TGF)-β. CD4⁺ T cells were co-cultured with bacterial lysate-pulsed APCs and assayed for cytokine production, FoxP3 expression, and TGF-β-mediated Smad signaling.

CD4⁺ cells from GF or SPF IL-10^−/− or wild-type mice induced more severe colitis and higher levels of inflammatory cytokines in IL-10^−/−, Rag2^−/− mice than in IL-10-replete, Rag2^−/− mice. Co-cultures of IL-10^−/− or wild-type CD4⁺ T cells plus bacterial lysate-pulsed APCs from IL-10^−/− mice contained more interferon (IFN)-γ, IL-12/23p40, and IL-17 than co-cultures of the same T cells plus APCs from wild-type mice. CD11b⁺ APCs were required for these effects. Blocking IL-10 receptors increased production of IFN-γ and IL-12/23p40 whereas exogenous IL-10 suppressed these cytokines. IL-10–producing APCs induced TGF-β-mediated, retinoic acid-dependent, differentiation of FoxP3⁺ Treg cells, whereas blocking the retinoic acid receptor, in vitro and in vivo, reduced proportions of FoxP3⁺ Treg cells.

IL-10 produced by APCs regulates homeostatic T-cell responses to commensal bacteria.