Regulation of CD8+ T Lymphocyte Fate Specification by Proteasome Activity and Cellular Metabolism

In an immune response, CD8+ T lymphocytes can differentiate into effector cells that acutely clear the infection as well as memory cells that provide lasting immunity against the same pathogen. Previous studies have shown that differentiation of CD8+ T cells in to effector and memory subsets occurs in a heterogeneous manner. Single-cell RNA-seq has revealed that transcriptional heterogeneity is present as early as the first cell division. Using single-cell transcriptional profiling to create supervised classifiers revealed that the outcome of intermediate-stage cells could be predicted. In ‘pre-effector’ and ‘pre-memory’ cells resulting from the first CD8+ T cell division in vivo, we observed distinctly low and high levels of proteasome activity, respectively. Pharmacological inhibition of proteasome activity early during differentiation resulted in acquisition of terminal effector cell characteristics, while enhancement of proteasome activity conferred attributes of memory lymphocytes. Transcriptomic and proteomic analyses revealed that modulation of proteasome activity in CD8+ T cells affected cellular metabolism. These metabolic changes were mediated, in part, through differential expression of Myc, a transcription factor that controls glycolysis and metabolic reprogramming. Overall, these findings demonstrate that proteasome activity is an important regulator of CD8+ T cell fate early during the differentiation process