T-bet regulates the fate of Th1 and Th17 lymphocytes in autoimmunity.
IL-17-producing T cells (Th17) have recently been implicated in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), an animal model for the human disease multiple sclerosis. However, little is known about the transcription factors that regulate these cells. Although it is clear that the transcription factor T-bet plays an essential role in the differentiation of IFN-gamma-producing CD4(+) Th1 lymphocytes, the potential role of T-bet in the differentiation of Th17 cells is not completely understood. In this study, therapeutic administration of a small interfering RNA specific for T-bet significantly improved the clinical course of established EAE. The improved clinical course was associated with suppression of newly differentiated T cells that express IL-17 in the CNS as well as suppression of myelin basic protein-specific Th1 autoreactive T cells. Moreover, T-bet was found to directly regulate transcription of the IL-23R, and, in doing so, influenced the fate of Th17 cells, which depend on optimal IL-23 production for survival. We now show for the first time that suppression of T-bet ameliorates EAE by limiting the differentiation of autoreactive Th1 cells, as well as inhibiting pathogenic Th17 cells via regulation of IL-23R.
Gocke
Anne R
AR
Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Cravens
Petra D
PD
Ben
Li-Hong
LH
Hussain
Rehana Z
RZ
Northrop
Sara C
SC
Racke
Michael K
MK
Lovett-Racke
Amy E
AE
D000818:Animals; D015551:Autoimmunity; D002454:Cell Differentiation / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000209:etiology / Q000276:immunology; D005786:Gene Expression Regulation; D006801:Humans; D020381:Interleukin-17; D053759:Interleukin-23 / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D004676:Myelin Basic Protein; D009419:Nerve Tissue Proteins / Q000276:immunology; D034741:RNA, Small Interfering / Q000494:pharmacology / Q000627:therapeutic use; D020825:T-Box Domain Proteins / Q000276:immunology / Q000502:physiology*; D016176:T-Lymphocyte Subsets / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*; D014157:Transcription Factors / Q000276:immunology; D000098815:T-bet Transcription Factor
D020381:Interleukin-17; D053759:Interleukin-23; C499047:Mbp protein, mouse; D004676:Myelin Basic Protein; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D014157:Transcription Factors