Colitogenic CD4⁺ T cells Expand via Direct MyD88-Dependent Toll-Like Receptor Pathway in Inflammatory Bowel Disease

Abstract

Inflammatory bowel diseases (IBD) are caused by excessive tissue damage through chronic inflammatory responses in the gut wall, and commonly take persistent courses. According to present understanding, the diseases are caused by infiltrated colitogenic effector/memory CD4⁺ T cells within the inflamed mucosa, which are presumably primed by commensal antigen-loading dendritic cells in lymphoid tissues. However, the nature of colitogenic CD4⁺ T cells over time during chronic colitis under the persistent presence of commensal bacteria remains largely unknown. Toll-like receptors (TLRs) that mediate the recognition of pathogen-associated molecular patterns (PAMPs) are widely expressed on/in cells of the innate immune system. However, recent findings have demonstrated 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. We here 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 (LP) CD4⁺CD44^high memory cells expressed a wide variety of TLRs along with MyD88, a key adaptor molecule required for signal transduction through TLRs. Although RAG-2^-/- mice with adoptive transfer of MyD88^-/- CD4⁺CD45RB^high cells developed colitis, the severity was reduced with delayed kinetics of clinical course, and the expansion of colitogenic CD4⁺ T cells was significantly impaired as compared with control mice with adoptive transfer of MyD88^+/+ CD4⁺CD45RB^high cells. When RAG-2^-/- mice received the same number of MyD88^+/+ (Ly5.1⁺) and MyD88^-/- (Ly5.2⁺) CD4⁺CD45RB^high cells, MyD88^-/- CD4⁺ T cells showed significantly lower proliferative responses as assessed by the in vivo CFSE division assay, lower expression of anti-apoptotic Bcl-2/Bcl-xL molecules and less production of IFN-γ and IL-17, compared to recipients of paired MyD88^+/+ CD4⁺ T cells. In conclusion, we demonstrated that the MyD88-dependent pathway, which mediates downstream signals of TLRs, is crucially involved in the proliferative and survival responses of colitogenic CD4⁺ T cells which are required for the perpetuation of chronic colitis. Thus, in addition to the specific commensal antigens, homeostatic cytokines, and co-stimulatory molecules, therapeutic approaches targeting PAMPs may be feasible in the treatment of IBD.