Vacuolar ATPase a2-subunit is a multifocal regulator of T cell development

Abstract

Abstract T cells are required for nearly all aspects of the adaptive immune response, and as such, their development into functional maturity is a complex and tightly controlled process. Developing thymocytes must coordinate a host of transcriptional, metabolic, and proliferative changes as they mature, and disturbances in this process underlie a number of diseases and syndromes, including cancers, immunodeficiencies, and autoimmunity. Interestingly, our recent work has identified an essential role for the a2-subunit isoform of the vacuolar ATPase (a2V) – a highly conserved intracellular proton pump – in orchestrating critical changes at multiple points of murine αβ T cell development. Cre-recombinase mediated deletion of a2V restricted to the hematopoietic compartment or immature thymocytes leads to a profound peripheral lymphopenia specifically confined to CD4+ and CD8+ αβ T cells, a condition originating from several deficiencies in intrathymic T cell development. Thymuses of a2V-deficient mice are reduced in size and cellularity, observations temporally correlated with the timing of a2V deletion. These deficiencies are in part tied to perturbations within the Notch1 signaling pathway, and obstructions at the β-selection checkpoint and a near complete failure of positive selection suggest further deficiencies in proliferative and TCR-mediated pathways, and therefore a broad and multifaceted role for a2V during early T cell development. Importantly, these data support a recent focus on V-ATPase as a chemotherapeutic target, and furthermore suggest that a2V may be a specific and efficacious target for combating proliferative potential of autoreactive or malignant T cells.