Toll-like receptor 4 signaling on CD4+ T cells plays a regulatory role in inflammatory bowel disease

Toll-like Receptors (TLRs) are a set of pathogen recognition receptors which are well characterized in dendritic cells and macrophages as important mediators of the innate immune system. With TLRs being recently identified on T cells, we show that TLR4 stimulation on CD4+ T cells regulates their ability to provoke intestinal inflammation. Using the IL-10 deficient model of colitis we show that Il10-/-/Tlr4-/- mice develop spontaneous colitis as early as 8 weeks while Il10-/- mice do not develop colitis even by 8 months. Similar results were obtained using the adoptive transfer model of colitis in which we transferred Il10-/-/Tlr4-/- or Il10-/- naïve CD4+ T cells into Rag1-/- recipients. Il10-/-/Tlr4-/- naïve CD4 + T cells induced more colitis than their Il10-/- counterparts. Mechanistically, LPS stimulation of TLR4 induces MKP-3 which inactivates ERK, resulting in less potent T cell activation. Collectively, our data suggests that TLR4 signaling plays an inhibitory role on subsequent T cell receptor (TCR) signaling and ultimately regulates activation of CD4+ T cel