TY - JOUR
T1 - T Helper 17 Lineage Differentiation Is Programmed by Orphan Nuclear Receptors RORα and RORγ
AU - Yang, Xuexian O.
AU - Pappu, Bhanu P.
AU - Nurieva, Roza
AU - Akimzhanov, Askar
AU - Kang, Hong Soon
AU - Chung, Yeonseok
AU - Ma, Li
AU - Shah, Bhavin
AU - Panopoulos, Athanasia D.
AU - Schluns, Kimberly S.
AU - Watowich, Stephanie S.
AU - Tian, Qiang
AU - Jetten, Anton M.
AU - Dong, Chen
N1 - Funding Information:
We thank B. Marzolf in Institute for Systems Biology for his assistance in microarray analysis, K. Murphy for RV-GFP vector, S. Reiner for advice on dual retroviral transduction, and the Dong lab members for their help. The work is supported by research grants from the National Institutes of Heath (NIH) (AR050772 to C.D. and an Intramural Research Program of the National Institute of Environment Health Sciences to A.M.J.) and the M.D. Anderson Cancer Center (to S.S.W.). R.N. received a postdoctoral fellowship from the Arthritis Foundation and is a recipient of a Scientist Development Grant from the American Heart Association. B.P. receives an Odyssey Fellowship of the M.D. Anderson Cancer Center. A.D.P. receives an NIH predoctoral training grant and an American Legion Auxiliary Award. C.D. and K.S.S. are M.D. Anderson Cancer Center Trust Fellows, and C.D. is a Cancer Research Institute Investigator and an American Lung Association Career Investigator.
PY - 2008/1/18
Y1 - 2008/1/18
N2 - T cell functional differentiation is mediated by lineage-specific transcription factors. T helper 17 (Th17) has been recently identified as a distinct Th lineage mediating tissue inflammation. Retinoic acid receptor-related orphan receptor γ (RORγ) was shown to regulate Th17 differentiation; RORγ deficiency, however, did not completely abolish Th17 cytokine expression. Here, we report Th17 cells highly expressed another related nuclear receptor, RORα, induced by transforming growth factor-β and interleukin-6 (IL-6), which is dependent on signal transducer and activator of transcription 3. Overexpression of RORα promoted Th17 differentiation, possibly through the conserved noncoding sequence 2 in Il17-Il17f locus. RORα deficiency resulted in reduced IL-17 expression in vitro and in vivo. Furthermore, RORα and RORγ coexpression synergistically led to greater Th17 differentiation. Double deficiencies in RORα and RORγ globally impaired Th17 generation and completely protected mice against experimental autoimmune encephalomyelitis. Therefore, Th17 differentiation is directed by two lineage-specific nuclear receptors, RORα and RORγ.
AB - T cell functional differentiation is mediated by lineage-specific transcription factors. T helper 17 (Th17) has been recently identified as a distinct Th lineage mediating tissue inflammation. Retinoic acid receptor-related orphan receptor γ (RORγ) was shown to regulate Th17 differentiation; RORγ deficiency, however, did not completely abolish Th17 cytokine expression. Here, we report Th17 cells highly expressed another related nuclear receptor, RORα, induced by transforming growth factor-β and interleukin-6 (IL-6), which is dependent on signal transducer and activator of transcription 3. Overexpression of RORα promoted Th17 differentiation, possibly through the conserved noncoding sequence 2 in Il17-Il17f locus. RORα deficiency resulted in reduced IL-17 expression in vitro and in vivo. Furthermore, RORα and RORγ coexpression synergistically led to greater Th17 differentiation. Double deficiencies in RORα and RORγ globally impaired Th17 generation and completely protected mice against experimental autoimmune encephalomyelitis. Therefore, Th17 differentiation is directed by two lineage-specific nuclear receptors, RORα and RORγ.
KW - MOLIMMUNO
UR - http://www.scopus.com/inward/record.url?scp=37849048599&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=37849048599&partnerID=8YFLogxK
U2 - 10.1016/j.immuni.2007.11.016
DO - 10.1016/j.immuni.2007.11.016
M3 - Article
C2 - 18164222
AN - SCOPUS:37849048599
SN - 1074-7613
VL - 28
SP - 29
EP - 39
JO - Immunity
JF - Immunity
IS - 1
ER -