RORgT modulates key features in adult thymopoiesis (HEM2P.235)

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Abstract Recent studies have elucidated the molecular mechanism of RORgT transcriptional network controlling Th17 cell lineage fate and effector function. RORgT was initially identified as a transcription factor required for thymopoiesis by maintaining survival of CD4+CD8+ (DP) thymocytes. There are increasing efforts to target RORgT for the treatment of autoimmune disorders, but it remains unclear how inhibition of RORgT in adult animals may impact thymic T cell development. Here, we show that RORgT is required to maintain adult thymopoiesis using both ERT2-CRE-mediated conditional genetic ablation and pharmacological inhibition with a selective small-molecule antagonist. RNA-SEQ analysis demonstrated that RORgT regulates thymocyte migration, positive selection, proliferation, inflammation and DNA synthesis involved in thymopoiesis beyond DP cell survival. RORgT also directly engages multiple target DNA in close proximity to key transcription factors such as T cell factor-1, Ikaros family zink finger protein 1 and others required for thymocyte development. Our work illustrates a new perspective in thymic development by showing that RORgT modulates adult thymopoiesis via cooperation with other major transcription factors.

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