Inhaltszusammenfassung

Smad7 negatively controls the anti-inflammatory cytokine transforming growth factor-β (TGF-β) signalling. Previous work suggested a role for Smad7 in the generation of auto-reactive T cells. However, the role of Smad7 in dendritic cells (DCs) remains elusive and was addressed in this thesis by using a conditional DC-specific Smad7 knockout mouse model (S7ΔDC mice). In response to both TGF-β or IFN-γ, Smad7-deficiency in DCs resulted in elevated expression of the transcription factors Batf3 an...Smad7 negatively controls the anti-inflammatory cytokine transforming growth factor-β (TGF-β) signalling. Previous work suggested a role for Smad7 in the generation of auto-reactive T cells. However, the role of Smad7 in dendritic cells (DCs) remains elusive and was addressed in this thesis by using a conditional DC-specific Smad7 knockout mouse model (S7ΔDC mice). In response to both TGF-β or IFN-γ, Smad7-deficiency in DCs resulted in elevated expression of the transcription factors Batf3 and IRF8, which are important for CD8+ CD103+ DC development. During steady state loss of Smad7 increased CD8+ CD103+ DC frequencies in the spleen, yet did not affect T cell development and function. Moreover, Smad7- deficient DCs expressed higher levels of indoleamine 2,3-dioxygenase (IDO), an enzyme involved in tryptophan catabolism and associated with tolerance induction. Mice devoid of Smad7 specifically in DCs developed attenuated experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. Analysis of central nervous system (CNS) infiltrating lymphocytes at the peak of disease revealed a significant increase of protective regulatory T cells (Tregs) and reduction of encephalitogenic effector T cells. Inhibition of IDO activity using 1-Methyl-D-Tryptophan (1-MT) restored susceptibility to EAE. Similarly, antibody-mediated depletion of Tregs (PC61) aggravated disease progression in S7ΔDC mice. Intriguingly, mice harbouring a DC-specific loss of IFN-γR2 and Smad7 were susceptible to EAE, suggesting that reduced susceptibility of S7ΔDC mice is predominantly mediated by an IFN-γ dependant mechanism. In conclusion, the data presented in this thesis indicates a previously unappreciated effect of Smad7 on DC subset differentiation. Absence of Smad7 promotes a tolerogenic DC phenotype in vivo, which can be further exploited for therapeutic intervention during autoimmune disorders.» weiterlesen» einklappen

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DDC Sachgruppe:
Biowissenschaften, Biologie