TGF-beta signaling in dendritic cells is a prerequisite for the control of autoimmune encephalomyelitis.
One unresolved issue in immune tolerance is what prevents self-reactive T cells from activation. In this study, we used a transgenic mouse model of targeted functional inactivation of TGF-betaR signaling in CD11c(+) cells (CD11c(dnR) mice) and showed a direct impact on the development of experimental autoimmune encephalomyelitis (EAE). We found that MOG(35-55) immunization of CD11c(dnR) mice results in strong inflammation of CNS, high frequency of T cells in CNS, increased levels of T helper 1 (T(H)1) and T(H)17 cytokines in the periphery, and lack of remission from EAE. Once crossed with mice prone to autoimmunity, double-transgenic CD11c(dnR)Mog(TCR) mice revealed a spontaneous EAE-like disease characterized by early infiltration of activated myelin-specific T cells into CNS, activation of microglial cells, inflammation of CNS, dysfunction of locomotion, and premature death. We constructed chimeric mice and demonstrated that inactivation of TGF-betaR signaling in dendritic cells (DCs) results in augmented EAE-associated T cell responses. Our data provide direct evidence that TGF-beta can control autoimmunity via actions on DCs.
Laouar
Yasmina
Y
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
Town
Terrence
T
Jeng
David
D
Tran
Elise
E
Wan
Yisong
Y
Kuchroo
Vijay K
VK
Flavell
Richard A
RA
D019264:Adoptive Transfer; D000704:Analysis of Variance; D000818:Animals; D002490:Central Nervous System / Q000276:immunology / Q000473:pathology; D003713:Dendritic Cells / Q000378:metabolism*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000378:metabolism*; D006023:Glycoproteins / Q000276:immunology*; D007108:Immune Tolerance / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D006023:Glycoproteins; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D016212:Transforming Growth Factor beta; C445081:myelin oligodendrocyte glycoprotein (35-55)