Retinoid-Related Orphan Receptor Controls Immunoglobulin Production and Th1/Th2 Cytokine Balance in the Adaptive Immune Response to Allergen1

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. ROR, 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 ROR-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 ROR, low-grade pulmonary inflam- mation was observed and characterized by the perivascular accumulation of B and T lymphocytes, increased numbers of inflam- matory 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- and IL-10 production was markedly greater in splenocytes from ROR-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 ROR- deficient animals in vivo. These data reveal a critical role for ROR in the regulation of Ig production and Th1/Th2 balance in adaptive immunity. The Journal of Immunology, 2007, 178: 3208 -3218.