TLR4/TRIF/IL15-dependent activation leads to diminished TGFβ signaling in dendritic cells; contribution to T-cell-mediated autoimmune inflammation in the gut.

TGFβ signaling in DCs is critical for the maintenance of self-tolerance. Here, we describe that in experimental colitis, DCs migrating to mesenteric lymph nodes show diminished levels of pSmad2. LPS- or poly(I:C)-induced activation of bone marrow-derived DC in vitro leads to refractory response to TGFβ stimulation in a TRIF-dependent and MyD88-independent fashion. Maturation of BMDC was associated with increased expression of IL15 and IL15Rα, and antibody blocking IL15/IL15Rα complex restored post-LPS TGFβ signaling. To determine the consequences of reduced TGFβ in DC in T-cell mediated colitis, we crossed Tgfbr2^ΔDC mice (JI 2012,189:3878) with Rag2^-/- mice and adoptively transferred CD4⁺, CD8⁺, and CD3⁺ T cells from naïve mice. Only CD4 (or 1:1 mix CD4⁺ + CD8⁺) T cells were required to induce colonic pathology, in addition to pancreatitis and hepatitis. CD3⁺ T-cell transfer induced a significant increase in cDC and pDC expression of MHCII, CD80, CD86, and CD40 in Cre⁺ mice. Co-transfer of WT CD8⁺ with CD40L^-/-CD4⁺ T –cells did not induce auto-inflammatory response in recipient mice. In conclusion, DC maturation results in IL15-mediated refractory response to TGFβ. Reduced TGFβ signaling in DC leads to CD4⁺ and CD8⁺ T cell-dependent inflammation and requires intact CD40L expression in CD4⁺ lymphocytes.