Retinoid-related orphan receptor gamma controls immunoglobulin production and Th1/Th2 cytokine balance in the adaptive immune response to allergen.
The retinoid-related orphan receptors (ROR) comprise a distinct subfamily of nuclear receptors with the capacity to act as both repressors and activators of transcription. RORgamma, the most recently identified member of the ROR family, has been shown to be important for the development of normal lymphocyte compartments as well as organogenesis of some lymphoid organs. In this report, we examine the capacity of RORgamma-deficient mice to develop an adaptive immune response to Ag using OVA-induced inflammation in mice as a model for allergic airway disease. In sham-treated mice lacking RORgamma, low-grade pulmonary inflammation was observed and characterized by the perivascular accumulation of B and T lymphocytes, increased numbers of inflammatory cells in the lung lavage fluid, and polyclonal Ig activation. Following sensitization and challenge, the capacity of these animals to develop the allergic phenotype was severely impaired as evidenced by attenuated eosinophilic pulmonary inflammation, reduced numbers of CD4+ lymphocytes, and lower Th2 cytokines/chemokine protein and mRNA expression in the lungs. IFN-gamma and IL-10 production was markedly greater in splenocytes from RORgamma-deficient mice following in vitro restimulation with OVA compared with wild-type splenocytes, and a shift toward a Th1 immune response was observed in sensitized/challenged RORgamma-deficient animals in vivo. These data reveal a critical role for RORgamma in the regulation of Ig production and Th1/Th2 balance in adaptive immunity.
Tilley
Stephen L
SL
Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of North Carolina, Chapel Hill, NC 27599, USA. stephen_tilley@med.unc.edu
Jaradat
Maisa
M
Stapleton
Cliona
C
Dixon
Darlene
D
Hua
Xiaoyang
X
Erikson
Christopher J
CJ
McCaskill
Joshua G
JG
Chason
Kelly D
KD
Liao
Grace
G
Jania
Leigh
L
Koller
Beverly H
BH
Jetten
Anton M
AM
D000485:Allergens / Q000276:immunology* / Q000633:toxicity; D000818:Animals; D000917:Antibody Formation / Q000235:genetics / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology; D016753:Interleukin-10 / Q000276:immunology; D051379:Mice; D008817:Mice, Mutant Strains; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D018168:Receptors, Retinoic Acid / Q000172:deficiency / Q000276:immunology*; D011988:Receptors, Thyroid Hormone / Q000172:deficiency / Q000276:immunology*; D012130:Respiratory Hypersensitivity / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology* / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology* / Q000473:pathology
D000485:Allergens; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; C539901:Rorc protein, mouse; D016753:Interleukin-10; D007371:Interferon-gamma