<i>Rroid2</i> regulates effector-to-memory CD8 ⁺ T cell differentiation during infection in vivo

CD8⁺ T cell differentiation has been associated with changes in the expression of long noncoding RNAs (lncRNAs). Yet, which and how lncRNAs regulate CD8⁺ T cell responses following infection in vivo remains incompletely understood. We performed deep RNA-seq to map the lncRNA expression landscape of CD8⁺ T cell subsets during infection and generated lncRNA knockout mouse models to evaluate the in vivo relevance of six lncRNAs. We identified <i>Rroid2</i> to regulate effector CD8⁺ T cell function and effector-to-memory differentiation. <i>Rroid2</i>-deficient mice displayed increased CD44^dim Foxp3⁺ regulatory T cells while the development of other immune cells, such as natural killer cells, was not affected. In CD8⁺ T cells, <i>Rroid2</i> deficiency resulted in a fine-tuned downregulation of transcription factors Id2 and T-bet and impaired KLRG1⁺ and KLRG1^- effector CD8⁺ T cell proliferation and cytotoxicity as well as effector-to-memory CD8⁺ T cell differentiation. The human orthologue of <i>Rroid2</i>, <i>LINC01814</i>, is also upstream of the transcriptional regulator <i>ID2</i> and is highly expressed in human memory CD8⁺ T cells. Taken together, <i>Rroid2</i> represents a key regulatory layer that controls CD8⁺ T cell differentiation.