Mechanistic Connections between Metabolic and Differentiation Programs in T Cells

Cellular metabolism is closely coupled to differentiation gene programs in many developmental systems. In part, this is due to a similar complement of transcription factors playing dual roles in regulating both the gene expression programs associated with specific metabolic pathways and the differentiation gene program of the cell. In T cells, T cell receptor- (TCR) and IL-2-sensitive transcription factors coordinate the programming of metabolic states with the effector and memory gene programs. Currently, our understanding of the mechanisms by which metabolic states contribute to the regulation of T cell differentiation gene programs is unclear.

Metabolites are directly involved in epigenetic modifying complexes and epigenetic modifications, but exactly how they are targeted to promote context dependent gene expression is largely unknown. The IL-2 sensitive metabolite alpha-ketoglutarate (αKG) is a cofactor for both histone and DNA demethylase complexes. We found that portions of the IL-2-sensitive effector gene program in CD4+ Th1 and CD8+ Tc1 cells are regulated by glutamine and αKG-induced events. This appears to be partially through events associated with DNA and histone methylation. In addition, we identified a novel mechanism by which IL-2- and αKG-sensitive metabolic changes regulate the association of CTCF with select genomic sites. CTCF is a transcription factor important in cellular differentiation and plays a pivotal role in genome organization. Our data show that a subset of CTCF sites is sensitive to IL-2- and αKG- metabolic changes in T cells. αKG-sensitive CTCF sites were often associated with loci containing IL-2- and αKG-sensitive genome organization patterns and gene expression in T cells. Surprisingly, IL-2- and αKG-sensitive CTCF sites in T cells were also associated with genes from developmental pathways that had αKG-sensitive expression in ES cells. The data collectively support a novel mechanism wherein CTCF serves to translate αKG-sensitive metabolic changes into context-dependent differentiation gene programs. Elucidating the mechanistic connections between metabolism and T cell programming might provide avenues to repurpose metabolic inhibitors used in cancer to dampen the effector T cell response in autoimmune disorders. These concepts could also improve the design of vaccines to induce a better memory response.