Retinoic acid can enhance conversion of naive into regulatory T cells independently of secreted cytokines.
It has been reported that retinoic acid (RA) enhances regulatory T (T reg) cell conversion by inhibiting the secretion of cytokines that interfere with conversion. This report shows that these conclusions provide a partial explanation at best. First, RA not only interfered with cytokine secretion but also with the ability of these cytokines to inhibit T reg cell conversion of naive T cells. Furthermore, RA enhanced conversion even in the absence of inhibitory cytokines. The latter effect depended on the RA receptor alpha (RAR alpha) but did not require Smad3, despite the fact that RA enhanced Smad3 expression. The RAR alpha 1 isoform was not essential for RA-dependent enhancement of transforming growth factor beta-driven conversion, suggesting that conversion can also be mediated by RAR alpha 2. Interleukin (IL)-6 strongly reduced RAR alpha expression levels such that a deficiency of the predominant RAR alpha 1 isoform leaves too little RAR alpha 2 for RA to inhibit the generation of Th17 cells in the presence of IL-6.
Nolting
Jens
J
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Daniel
Carolin
C
Reuter
Sabine
S
Stuelten
Christina
C
Li
Peng
P
Sucov
Henry
H
Kim
Byung-Gyu
BG
Letterio
John J
JJ
Kretschmer
Karsten
K
Kim
Hye-Jung
HJ
von Boehmer
Harald
H
D000818:Animals; D016207:Cytokines / Q000502:physiology*; D018960:Hyaluronan Receptors / Q000032:analysis; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018168:Receptors, Retinoic Acid / Q000502:physiology; D000072482:Retinoic Acid Receptor alpha; D051900:Smad3 Protein / Q000502:physiology; D051901:Smad4 Protein / Q000502:physiology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects*; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014212:Tretinoin / Q000494:pharmacology*
C476399:Cd44 protein, mouse; D016207:Cytokines; D018960:Hyaluronan Receptors; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D016212:Transforming Growth Factor beta; D014212:Tretinoin