TLRs that mediate the recognition of pathogen-associated molecular patterns are widely expressed on/in cells of the innate immune system. However, recent findings demonstrate that certain TLRs are also expressed in conventional TCRαβ+ T cells that are critically involved in the acquired immune system, suggesting that TLR ligands can directly modulate T cell function in addition to various innate immune cells. In this study, we report that in a murine model of chronic colitis induced in RAG-2−/− mice by adoptive transfer of CD4+ CD45RB high T cells, both CD4+ CD45RB high donor cells and the expanding colitogenic lamina propria CD4+ CD44 high memory cells expresses a wide variety of TLRs along with MyD88, a key adaptor molecule required for signal transduction through TLRs. Although RAG-2−/− mice transferred with MyD88−/− CD4+ CD45RB high cells developed colitis, the severity was reduced with the delayed kinetics of clinical course, and the expansion of colitogenic CD4+ T cells was significantly impaired as compared with control mice transferred with MyD88+/+ CD4+ CD45RB high cells. When RAG-2−/− mice were transferred with the same number of MyD88+/+(Ly5. 1+) and MyD88−/−(Ly5. 2+) CD4+ CD45RB high cells, MyD88−/− CD4+ T cells showed significantly lower proliferative responses assessed by in vivo CFSE division assay, and also lower expression of antiapoptotic Bcl-2/Bcl-x L molecules and less production of IFN-γ and IL-17, compared with the paired MyD88+/+ CD4+ T cells. Collectively, the MyD88-dependent pathway that controls TLR signaling in T cells may directly promote the proliferation and survival of colitogenic CD4+ T cells to sustain chronic colitis.