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Lymphocyte Development and Function in the Absence of Retinoic Acid-Related Orphan Receptor ¹

Ivan Dzhagalov^*, Vincent Giguère and You-Wen He^2,*

^* Department of Immunology, Duke University Medical Center, Durham, NC 27710; and Molecular Oncology Group, McGill University Health Center, Montreal, Quebec, Canada

The orphan nuclear receptor, retinoid acid-related orphan receptor (ROR), is essential for the development of cerebellar Purkinje cells and bone tissue. ROR may also play a critical role in lymphocyte development and function because staggerer mice, a natural mutant strain with a disrupted expression of ROR, have reduced thymic and splenic cellularity. In this report, we analyzed the role of ROR in lymphocyte development by examining lymphoid compartments in ROR^–/– mice and Rag-2^–/– mice reconstituted with ROR^–/– bone marrow. We found that T and B cell development was severely defective in ROR^–/– mice, but not in Rag-2^–/–/ROR^–/– chimeric mice. We also analyzed cellular and humoral immune responses in Rag-2^–/–/ROR^–/– chimeric mice. Our results show that serum IgG levels were elevated in Rag-2^–/–/ROR^–/– chimeric mice after immunization with a T-dependent Ag compared with control chimeras. IFN- production by ROR^–/– CD8⁺ T cells after TCR stimulation was also increased. Furthermore, ROR^–/– mast cells and macrophages produced an increased amount of TNF- and IL-6 upon activation. These results indicate that ROR indirectly regulates lymphocyte development by providing an appropriate microenvironment and controls immune responses by negatively regulating cytokine production in innate immune cells and lymphocytes.

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