Format

Send to

Choose Destination
See comment in PubMed Commons below
J Leukoc Biol. 2014 Nov;96(5):895-905. doi: 10.1189/jlb.3A0114-056RR. Epub 2014 Jul 11.

TLR4 regulates IFN-γ and IL-17 production by both thymic and induced Foxp3+ Tregs during intestinal inflammation.

Author information

1
Departments of Microbiology and Immunology and.
2
Department of Pathology, The University of Chicago, Chicago, Illinois, USA;
3
Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University, Shanghai; and.
4
Departments of Cell Biology and.
5
Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, USA.
6
Departments of Microbiology and Immunology and Pathology, The University of Texas Medical Branch, Galveston, Texas, USA; yicong@utmb.edu.

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.

KEYWORDS:

LPS; MyD88; SOCS3; colitis

PMID:
25015957
PMCID:
PMC4197555
DOI:
10.1189/jlb.3A0114-056RR
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Grant support

Publication types

MeSH terms

Substances

Grant support

PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire Icon for PubMed Central
    Loading ...
    Support Center