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 TCRalphabeta(+) 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-gamma 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.
Tomita
Takayuki
T
Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
Kanai
Takanori
T
Fujii
Toshimitsu
T
Nemoto
Yasuhiro
Y
Okamoto
Ryuichi
R
Tsuchiya
Kiichiro
K
Totsuka
Teruji
T
Sakamoto
Naoya
N
Akira
Shizuo
S
Watanabe
Mamoru
M
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002908:Chronic Disease; D003092:Colitis / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000276:immunology / Q000378:metabolism*
C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D051193:Toll-Like Receptors