MyD88-dependent pathway in T cells directly modulates the expansion of colitogenic CD4⁺ T cells in chronic colitis

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^hlgh 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 MyDSS^-/- (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. The Journal of Immunology, 2008, 180: