Elucidating the Transcriptional Role of the Nuclear Receptor RORα in CD8+ T Cell Memory vs Effector Cell Development

Abstract

Abstract CD8+ T cells play a critical role in controlling viral infections and cancer and have the potential to be harnessed for the development of new therapeutic strategies. Defining the transcriptional regulatory networks that control CD8+ T cell differentiation and function is of great importance to achieve these goals. The retinoic acid receptor-related orphan receptor alpha (RORα), a member of the nuclear receptor superfamily of ligand-regulated transcription factors, has emerged as a potential transcriptional regulator of CD8+ T cell immunity. However, exactly how RORα functions in these processes is poorly understood. To this end we seek to identify the transcriptional role of RORα in regulating the differentiation of memory CD8+ T cells. Utilizing a mouse model with T cell-specific deletion of RORα we identify that RORα deficiency in CD8+ T cells leads to increased IFNγ production and increased cell-specific cytolytic function in vitro. Conversely, RORα overexpression results in decreased IFNγ production and defects in proliferative capacity in vitro. Our in vivo data further reveals that deletion of RORα in CD8+ T cells may affect the trafficking of these cells to non-lymphoid tissue and play a role in the development of tissue resident memory (TRM) cells. Our study provides important insights into the role of RORα in regulating CD8+ T cell function and highlights the potential for targeting nuclear receptors in the development of novel cell-based therapeutics.