Metzler, Barbara, Gfeller, Patrick and Guinet, Elisabeth (2016) Restricting Glutamine or Glutamine-dependent purine and pyrimidine synthesis promotes human T regulator cells. The Journal of Immunology.

Abstract

T cell subsets may differ in their metabolic requirements, and further insight into such differences might be harnessed to selectively promote T regulator cells (Tregs) for therapies in autoimmunity and transplantation. We found that Glutamine (Gln) restriction during T cell activation favored CD4 T cells with high expression of the Treg transcription factor FOXP3. This resulted from reduced numbers and proliferation of activated FOXP3lo/- CD4 T cells while FOXP3hi CD4 T cell numbers increased at 10-20% of standard Gln. This increase was abolished by blocking Glutamine synthetase, an enzyme that responds to Gln and purine/pyrimidine deficiencies. The shift towards FOXP3hi CD4 T cells under low Gln was mimicked with inhibitors of Gln-dependent pyrimidine and purine syntheses that recapitulated changes in cell numbers and cell cycles, respectively, and was confirmed by siRNA knockdown of the respective rate-limiting Gln-consuming enzymes CAD and PPAT. The resulting FOXP3hi cell-enriched populations contained functional Tregs that inhibited the proliferation of primary T cells. They also produced effector cytokines, and subset analysis based on CTLA-4 expression revealed that IL-17 and IL-4 secretion were largely confined to CTLA-4hi CD4 T cells. With high IL-17 production by CTLA-4hi cells, suppression was more potent with or restricted to CD25hiCTLA-4lo CD4 T cells. Collectively these results show that impaired Gln-dependent de novo nucleotide synthesis promotes functional human FOXP3hi Tregs, yet also retains CTLA-4hi IL-17 + cells that may constrain regulation.

Item Type:	Article
Date Deposited:	29 Apr 2016 23:45
Last Modified:	29 Apr 2016 23:45
URI:	https://oak.novartis.com/id/eprint/26523