title: TLR4 regulates IFN-γ and IL-17 production by both thymic and induced Foxp3+ Tregs during intestinal inflammation.
abstract: 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. Treg production of the proinflammatory cytokines IFN-γ and/or IL-17 may arguably explain their ineffectiveness in suppressing intestinal inflammation. However, it remains unknown whether iTreg and tTreg produce proinflammatory cytokines and how TLR signaling regulates this process. Here, we found that Foxp3(+)Tregs were 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 Tregs within inflamed intestines. The majority of Foxp3(+) Tregs in the spleen was Helios(+)Nrp1(+), whereas most Foxp3(+) Tregs in the intestinal LP were Helios(-)Nrp1(-). More Helios(+)Nrp1(+) Tregs expressed IFN-γ and/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(+) tTregs and Helios(-)Nrp1(-) iTregs produce proinflammatory cytokines in the intestines during inflammation, which was regulated by TLR4 signaling.
authors.affiliation: Departments of Microbiology and Immunology and.
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Cao
authors.affiliation: Departments of Microbiology and Immunology and.
authors.forename: Suxia
authors.initials: S
authors.lastname: Yao
authors.affiliation: Department of Pathology, The University of Chicago, Chicago, Illinois, USA;
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Stefka
authors.affiliation: Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University, Shanghai; and.
authors.forename: Zhanju
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Departments of Cell Biology and.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Qin
authors.affiliation: Departments of Microbiology and Immunology and.
authors.forename: Houpu
authors.initials: H
authors.lastname: Liu
authors.affiliation: Departments of Microbiology and Immunology and.
authors.forename: Heather L
authors.initials: HL
authors.lastname: Evans-Marin
authors.affiliation: Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Charles O
authors.initials: CO
authors.lastname: Elson
authors.affiliation: Department of Pathology, The University of Chicago, Chicago, Illinois, USA;
authors.forename: Cathryn R
authors.initials: CR
authors.lastname: Nagler
authors.affiliation: Departments of Microbiology and Immunology and Pathology, The University of Texas Medical Branch, Galveston, Texas, USA; yicong@utmb.edu.
authors.forename: Yingzi
authors.initials: Y
authors.lastname: Cong
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism; D000818:Animals; D003092:Colitis / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D051858:Forkhead Transcription Factors / Q000378:metabolism; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D007371:Interferon-gamma / Q000096:biosynthesis*; D020381:Interleukin-17 / Q000096:biosynthesis*; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000276:immunology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D039942:Neuropilin-1 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D016207:Cytokines; D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; D018836:Inflammation Mediators; D007371:Interferon-gamma; D020381:Interleukin-17; D053594:Myeloid Differentiation Factor 88; D039942:Neuropilin-1; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D051197:Toll-Like Receptor 4; D014157:Transcription Factors; C498833:Foxp3 protein, mouse; C491411:Socs3 protein, mouse; C476286:Ticam1 protein, mouse; C491746:Zfpn1a2 protein, mouse
keywords: LPS; MyD88; SOCS3; colitis