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

Anthony T. Cao, Suxia Yao, Andrew T. Stefka, Zhanju Liu, Hongwei Qin, Houpu Liu, Heather L. Evans-Marin, Charles O. Elson, Cathryn R. Nagler, Yingzi Cong

Research output: Contribution to journalArticlepeer-review

32 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)895-905
Number of pages11
JournalJournal of Leukocyte Biology
Issue number5
StatePublished - Nov 1 2014


  • Colitis
  • LPS
  • MyD88
  • SOCS3

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Cell Biology


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