Retinoid-related orphan receptor γ (RORγ) adult induced knockout mice develop lymphoblastic lymphoma

ROR gamma is a nuclear hormone receptor which controls polarization of naive CD4+ T-cells into proinflammatory Th17 cells. Pharmacological antagonism of ROR gamma has therapeutic potential for autoimmune diseases; however, this mechanism may potentially carry target-related safety risks, as mice deficient in Rorc, the gene encoding ROR gamma, develop T-cell lymphoma with 50% frequency. Due to the requirement of ROR gamma during development, the Rorcknockout (KO) animals lack secondary lymphoid organs and have a dysregulation in the generation-of CD4+ and CD8 + T cells. We wanted to extend the evaluation of ROR gamma deficiency to address the question whether lymphomas, similar to those observed in the Rorc KO, would develop in an animal with an otherwise intact adult immune system. Accordingly, we designed a conditional ROR gamma knockout mouse (Rorc CKO) where the Rorc locus could be deleted in adult animals. Based on these studies we can confirm that these animals also develop lymphoma in a similar time frame as embryonic Rorc knockouts. This study also suggests that in animals where the gene deletion is incomplete, the thymus undergoes a rapid selection process replacing Rorc deficient cells with remnant thymocytes carrying a functional Rorc locus and that subsequently, these animals do not develop lymphoblastic lymphoma. (C) 2016 Elsevier B.V. All rights reserved.