T Cell Activation Triggers Reversible Inosine-5’-Monophosphate Dehydrogenase Assembly

T cell-mediated adaptive immunity requires naïve, unstimulated T cells to transition from a quiescent metabolic state into a highly proliferative state upon T cell receptor engagement. This complex process depends on transcriptional changes mediated by Ca2+-dependent NFAT signaling, mTOR-mediated signaling and increased activity of the guanine nucleotide biosynthetic enzyme inosine-5’-monophosphate (IMP) dehydrogenase (IMPDH). Inhibitors of these pathways serve as potent immunosuppressants. Unexpectedly, we discovered that all three pathways converge to promote the assembly of IMPDH protein into micron-scale macromolecular filamentous structures in response to T cell activation. Assembly is post-transcriptionally controlled by mTOR and the Ca2+ influx regulator STIM1. Furthermore, IMPDH assembly and catalytic activity were negatively regulated by guanine nucleotide levels, suggesting a negative feedback loop that limits biosynthesis of guanine nucleotides. Filamentous IMPDH may be more resistant to this inhibition, facilitating accumulation of the higher GTP levels required for T cell proliferation. Abbreviations IMP inosine-5’-monophosphate IMPDH inosine-5’-monophosphate dehydrogenase LCMV lymphocytic choriomeningitis virus MPA mycophenolic acid mTOR mechanistic target of rapamycin NFAT nuclear factor of activated T cells STIM1 stromal interaction molecule 1 STIM2 stromal interaction molecule 2 TCR T cell receptor