ABSTRACT
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 inosine-5′-monophosphate (IMP) dehydrogenase 1 and 2 enzymes (IMPDH1 and IMPDH2, hereafter 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.
Footnotes
Competing interests
The authors declare no competing or financial interests.
Author contributions
Conceptualization: K.C.D., J.M.K., J.S., G.F.R., J.R.P.; Methodology: K.C.D., Y.K., M.C.J., J.M.C., J.M.K., G.F.R., A.J.A., J.R.P.; Formal analysis: K.C.D., Y.K., M.C.J., J.M.C.; Investigation: K.C.D., Y.K., M.C.J., G.F.R.; Resources: J.S., G.F.R.; Data curation: K.C.D., Y.K., M.C.J., J.M.C.; Writing - original draft: K.C.D., J.R.P.; Writing - review & editing: K.C.D., Y.K., J.M.K., J.S., G.F.R., A.J.A., J.R.P.; Supervision: J.M.K., J.S., A.J.A., J.R.P.; Project administration: J.R.P.; Funding acquisition: K.C.D., J.M.K., J.S., G.F.R., A.J.A., J.R.P.
Funding
This work was supported by National Institutes of Health grants (GM083025 to J.R.P., T32 CA009035 to K.C.D., GM117907 to J.S., GM102503 to A.J.A. and GM118396 to J.M.K.), funds from the Pennsylvania Department of Health to J.R.P. and the F.M. Kirby Foundation to G.F.R., and a Fox Chase Cancer Center Board of Associates Postdoctoral Fellowship Award to K.C.D. Deposited in PMC for release after 12 months.
Supplementary information
Supplementary information available online at http://jcs.biologists.org/lookup/doi/10.1242/jcs.223289.supplemental
- Received August 1, 2018.
- Accepted August 6, 2018.
- © 2018. Published by The Company of Biologists Ltd
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