Ribonuclease inhibitor 1 (RNH1) mediated mRNA specific translation regulates peripheral CD8+ T- cell homeostasis 3544

Abstract Description CD8+ T cells are essential for immune defense against viral infections and cancers, with various mechanisms regulating their maintenance and function. While global translation is crucial for effector function, the role of selective mRNA translation in T cell homeostasis remains unclear. RNH1 is a vertebrate-specific gene involved in various biological processes. Our lab has shown that RNH1 is involved in selective translation. Recent clinical reports indicate that patients with RNH1 mutations suffer from recurrent viral infections and lymphopenia, suggesting a role for RNH1 in T cell biology. To investigate, we generated T cell-specific Rnh1 knockout (KO) mice by crossing Rnh1flox/flox with CD4-Cre+ mice. In line with clinical data, Rnh1 KO mice displayed a significant reduction in CD4+ and CD8+ T cells in peripheral lymphoid organs with a more pronounced loss of CD8+ T cells. We excluded thymic defects and found that RNH1 loss led to apoptosis of CD8+ T cells, indicating a disruption in homeostasis. Additionally, there was a marked reduction in CD44+ memory-like CD8+ T cells. Single-cell RNASeq analysis further supported these findings. At the molecular level, we observed that loss of RNH1 did not affect global translation but selectively decreased the expression of IL-15Ra and IL-7Rb receptors at the protein level, without altering mRNA expression. Collectively, our study identifies RNH1 as a novel regulator of CD8+ T- cell homeostasis through selective mRNA translation. Funding Sources Supported by Swiss National Science Foundation (PP00P3_190073; 320030-227461). Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)