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T LRs 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.