Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 120, Issue 2, Pages 570-581Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI40055
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Funding
- NIH [AI68685, DK35108, DK080506, CA133702]
- Crohn's and Colitis Foundation of America (CCFA)
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TLRs sense various microbial products. Their function has been best characterized in DCs and macrophages, where they act as important mediators of innate immunity. TLR4 is also expressed on CD4(+) T cells, but its physiological function on these cells remains unknown. Here, we have shown that TLR4 triggering on CD4+ T cells affects their phenotype and their ability to provoke intestinal inflammation. In a model of spontaneous colitis, Il10(-/-)Tlr4(-/-) mice displayed accelerated development of disease, with signs of overt colitis as early as 8 weeks of age, when compared with Il10(-/-) and Il10(-/-)Tlr9(-/-) mice, which did not develop colitis by 8 months. Similar results were obtained in a second model of colitis in which transfer of naive Il10(-/-)Tlr4(-/-) CD4(+) T cells into Rag1(-/-) recipients sufficient for both IL-10 and TLR4 induced more aggressive colitis than the transfer of naive Il10(-/-) CD4(+) T cells. Mechanistically, LPS stimulation of TLR4-bearing CD4(+) T cells inhibited ERK1/2 activation upon subsequent TCR stimulation via the induction of MAPK phosphatase 3 (MKP-3). Our data therefore reveal a tonic inhibitory role for TLR4 signaling on subsequent TCR-dependent CD4(+) T cell responses.
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