PIM kinase control of CD8 T cell protein synthesis and cell trafficking

Abstract

Integration of a large network of kinase signalling pathways co-ordinates changes in the transcription, translation and metabolic events required for T cell activation and differentiation. The present study explores the role of the Serine/Threonine kinases PIM1 and PIM2 in controlling murine CD8 T lymphocyte antigen receptor-mediated activation and differentiation in response to the cytokines Interleukin 2 (IL-2) or IL-15. We show that PIM kinases are dispensable for the differentiation programs controlled by the antigen-receptor and IL-15. There is however a selective role for the PIM kinases in the context of IL-2 regulation of CD8 T cell fate. One key insight was that the PIM kinases controlled the migratory capabilities of effector CD8 T cells, with Pim1 / Pim2 -deficient CD8 T cells unable to fully switch off the naïve T cell chemokine and adhesion receptor program during effector differentiation. PIM kinases were also needed for IL-2 to sustain high expression of the glucose transporters SLC2A1 and SLC2A3 and to maintain activity of the nutrient sensing kinase mTORc1. Strikingly, PIM kinases did not have a dominant impact on IL-2-driven transcriptional programs but rather selectively modulated protein synthesis to shape cytotoxic T cell proteomes. This study reveals a selective role of PIM kinases in IL-2 control of CD8 T cells and highlights how regulated changes in protein synthesis can impact T cell phenotypes.