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

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• 作者：Maria Liljevald^a ; ^{maria.liljevald@astrazeneca.com" class="auth_mail" title="E-mail the corresponding author} ; Maria Rehnberg^b ; Magnus Sö ; derberg^a ; Marie Ramnegå ; rd^b ; Jenny Bö ; rjesson^c ; Donatella Luciani^b ; Nina Krutrö ; k^b ; Lena Br&auml ; ndé ; n^a ; Camilla Johansson^a ; Xiufeng Xu^c ; Mikael Bjursell^c ; Anna-Karin Sjö ; gren^a ; Jorrit Hornberg^a ; Ulf Andersson^a ; David Keeling^b ; Johan Jirholt^b
• 关键词：NHR ; RORγ ; RORγt ; Rorc ; Th17 cells ; Adult induced knockout mouse model ; Lymphoblastic lymphoma
• 刊名：Autoimmunity Reviews
• 出版年：2016
• 出版时间：November 2016
• 年：2016
• 卷：15
• 期：11
• 页码：1062-1070
• 全文大小：1287 K

文摘

RORγ is a nuclear hormone receptor which controls polarization of naive CD4⁺ T-cells into proinflammatory Th17 cells. Pharmacological antagonism of RORγ has therapeutic potential for autoimmune diseases; however, this mechanism may potentially carry target-related safety risks, as mice deficient in Rorc, the gene encoding RORγ, develop T-cell lymphoma with 50% frequency. Due to the requirement of RORγ during development, the Rorc knockout (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 RORγ 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 RORγ 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.