Suppression of experimental autoimmune uveoretinitis by inducing differentiation of regulatory T cells via activation of aryl hydrocarbon receptor.
Purpose. Aryl hydrocarbon receptor (AHR) has been identified as a regulator of CD25(+)CD4(+) regulatory T-cell (T(reg)) and Th17 cell differentiation in mice, and activation of AHR by its ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces functional T(reg) cells. In this study, the authors examined whether the AHR-mediated effect of TCDD suppresses mouse experimental autoimmune uveitis (EAU) by inducing T(reg) cell differentiation. Methods. C57BL/6 mice were injected with TCDD 1 day before immunization with human interphotoreceptor retinoid-binding protein peptide 1-20 (hIRBP-p), and the severity of EAU was assessed clinically and histopathologically. Immunologic responses of draining lymph node cells and splenocytes to hIRBP-p and anti-CD3 monoclonal antibody (mAb) were assessed by T-cell proliferation and cytokine production. In addition, differentiation of Foxp3(+) T cells and their immunosuppressive roles in TCDD-injected mice were evaluated. Results. TCDD injection increased Foxp3(+) T cells in the lymph nodes and in the spleen. Development of EAU was completely suppressed by TCDD injection, and suppression was abolished by treatment with anti-CD25 mAb before TCDD injection. Both lymphocytes and splenocytes obtained from TCDD-injected mice immunized with hIRBP-p failed to produce IFN-gamma and IL-17 on stimulation with hIRBP-p, and the failure of IL-17 production was observed even when stimulated with anti-CD3 mAb. However, this protocol did not interfere with IL-10 production and T-cell proliferation response when assessed on stimulation with anti-CD3 mAb. Conclusions. Activation of AHR by TCDD markedly suppressed autoimmune uveoretinitis through mechanisms that expand CD25(+)Foxp3(+) T(reg) cells and interfere with the activation of Th1 and Th17 cells.
Zhang
Lina
L
Departments of Ophthalmology, Tokyo Medical University, Tokyo, Japan.
Ma
Juan
J
Takeuchi
Masaru
M
Usui
Yoshihiko
Y
Hattori
Takaaki
T
Okunuki
Yoko
Y
Yamakawa
Naoyuki
N
Kezuka
Takeshi
T
Kuroda
Masahiko
M
Goto
Hiroshi
H
D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology / Q000517:prevention & control*; D002454:Cell Differentiation / Q000187:drug effects*; D016207:Cytokines / Q000378:metabolism; D005136:Eye Proteins; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology*; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D012173:Retinitis / Q000276:immunology / Q000517:prevention & control*; D012177:Retinol-Binding Proteins; D013601:T-Lymphocytes / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014605:Uveitis / Q000276:immunology / Q000517:prevention & control*; D000099214:Retinol-Binding Proteins, Interstitial
D016207:Cytokines; D005136:Eye Proteins; D051858:Forkhead Transcription Factors; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D012177:Retinol-Binding Proteins; D000099214:Retinol-Binding Proteins, Interstitial; C498833:Foxp3 protein, mouse