TLR4 signaling in effector CD4+ T cells regulates TCR activation and experimental colitis in mice

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.