Tlr4 regulates IFN-γ and IL-17 production by both thymic and induced Foxp3+Tregsduring intestinal inflammation

Academic Article


  • Tregs play a crucial role in the maintenance of intestinal immune homeostasis. However, significant numbers of Foxp3+Tregs accumulate in the inflamed lesions in experimental colitis and in IBD patients. Tregproduction of the proinflammatory cytokines IFN-γ and/or IL-17 may arguably explain their ineffectiveness in suppressing intestinal inflammation. However, it remains unknown whether iTregand tTregproduce proinflammatory cytokines and how TLR signaling regulates this process. Here, we found that Foxp3+Tregswere increased in the intestines of B6.TLR4-/-and B6.IL-10-/-mice when compared with WT B6 mice. TLR4-/-and IL-10-/-resulted in more Tregswithin inflamed intestines. The majority of Foxp3+Tregsin the spleen was Helios-Nrp1-, whereas most Foxp3+Tregsin the intestinal LP were Helios+Nrp1+. More Helios-Nrp1-Tregsexpressed IFN-γand/or IL-17 than did Helios+Nrp1+Tregs in the spleen and intestine, which was increased with TLR4-/-. TLR4 signaling in T cells and APCs inhibited Foxp3+induction via MyD88-dependent, TRIF-independent pathways, which was negatively regulated by SOCS3. Collectively, these data demonstrate Helios+Nrp1+tTregsand Helios--Nrp1-iTregsproduce proinflammatory cytokines in the intestines during inflammation, which was regulated by TLR4 signaling.
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    Digital Object Identifier (doi)

    Author List

  • Cao AT; Yao S; Stefka AT; Liu Z; Qin H; Liu H; Evans-Marin HL; Elson CO; Nagler CR; Cong Y
  • Start Page

  • 895
  • End Page

  • 905
  • Volume

  • 96
  • Issue

  • 5