Abstract
Whereas TGF-beta is essential for the development of peripherally induced Foxp3(+) regulatory T cells (iTreg cells) and Th17 cells, the intracellular signaling mechanism by which TGF-beta regulates development of both cell subsets is less understood. In this study, we report that neither Smad2 nor Smad3 gene deficiency abrogates TGF-beta-dependent iTreg induction by a deacetylase inhibitor trichostatin A in vivo, although the loss of the Smad2 or Smad3 gene partially reduces iTreg induction in vitro. Similarly, SMAD2 and SMAD3 have a redundant role in development of Th17 in vitro and in experimental autoimmune encephalomyelitis. In addition, ERK and/or JNK pathways were shown to be involved in regulating iTreg cells, whereas the p38 pathway predominately modulated Th17 and experimental autoimmune encephalomyelitis induction. Therefore, selective targeting of these intracellular TGF-beta signaling pathways during iTreg and Th17 cell development might lead to the development of therapies in treating autoimmune and other chronic inflammatory diseases.
Publication types
-
Comparative Study
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Cell Differentiation / drug effects
-
Cell Differentiation / genetics
-
Cell Differentiation / immunology*
-
Encephalomyelitis, Autoimmune, Experimental / immunology
-
Encephalomyelitis, Autoimmune, Experimental / metabolism
-
Encephalomyelitis, Autoimmune, Experimental / pathology
-
Forkhead Transcription Factors / biosynthesis
-
Gene Knock-In Techniques
-
Hydroxamic Acids / pharmacology
-
Interleukin-17 / biosynthesis*
-
Mice
-
Mice, Inbred C57BL
-
Mice, Knockout
-
Mice, Transgenic
-
Receptors, Transforming Growth Factor beta / physiology
-
Signal Transduction / drug effects
-
Signal Transduction / genetics
-
Signal Transduction / immunology*
-
Smad2 Protein / deficiency
-
Smad2 Protein / genetics
-
Smad2 Protein / physiology*
-
Smad3 Protein / deficiency
-
Smad3 Protein / genetics
-
Smad3 Protein / physiology*
-
T-Lymphocytes, Helper-Inducer / cytology
-
T-Lymphocytes, Helper-Inducer / immunology*
-
T-Lymphocytes, Helper-Inducer / metabolism
-
T-Lymphocytes, Regulatory / drug effects
-
T-Lymphocytes, Regulatory / immunology*
-
T-Lymphocytes, Regulatory / metabolism
-
Transforming Growth Factor beta / physiology
Substances
-
Forkhead Transcription Factors
-
Foxp3 protein, mouse
-
Hydroxamic Acids
-
Interleukin-17
-
Receptors, Transforming Growth Factor beta
-
Smad2 Protein
-
Smad2 protein, mouse
-
Smad3 Protein
-
Smad3 protein, mouse
-
Transforming Growth Factor beta
-
trichostatin A