Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 105, Issue 31, Pages 10865-10870Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0805058105
Keywords
brain; CNS; spinal cord
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Funding
- Howard Hughes Medical Institute Funding Source: Medline
- NIAID NIH HHS [K99 AI072956-01A1, R00 AI072956, K99 AI072956, R00 AI072956-03, K99 AI072956-02] Funding Source: Medline
- NIA NIH HHS [4 R00 AG029726-02, R00 AG029726, 1 K99 AG029726-01, K99 AG029726] Funding Source: Medline
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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-beta R 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 CD11cdnR 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-beta R 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.
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