Ribosomal protein L22 (Rpl22) controls the development of αβ lineage T cells by regulating ER stress pathways (HEM4P.239)

Abstract

Abstract While mature αβ and γδ T cells arise from a common CD4-CD8- thymocyte progenitor, the pathways controlling separation of these lineages remain poorly understood. We have identified the ribosomal protein Rpl22, a novel effector that plays a crucial role in αβ T cell development, but is dispensable for γδ T cell development. Indeed, Rpl22-deficiency selectively blocks the development of αβ T cells at the β-selection checkpoint in a p53-dependent manner. Here, we investigate the basis for p53 induction caused by Rpl22-deficiency and its restriction to αβ T cell progenitors. We found that Rpl22 can directly bind and suppress the translation of p53 mRNA, and that the absence of Rpl22 induces p53 through translational de-repression. Rpl22 appears to specifically regulate p53 in αβ T cell progenitors by controlling the activity of signaling processes that induce p53, such as endoplasmic reticulum (ER) stress. αβ T cell development is dependent on the activation of ER stress responses, which are known to induce p53. Pharmacologic exacerbation of ER stress blocks development of αβ, but not γδ T cells. Moreover, Rpl22-inactivation exacerbates signals from all three known ER stress sensors (PERK, Ire1α, and ATF6). Finally, inhibiting the ER stress response mediated by PERK partially restores development of Rpl22-deficient αβ progenitors. Together, our data suggest that Rpl22 regulates αβ T cell development by controlling the physiologic ER stress upon which their development depends.