Abstract
Thymic regulatory T cells (tTregs) and induced regulatory T cells (iTregs) suppress murine acute graft-versus-host disease (GVHD). Previously, we demonstrated that the plasmacytoid dendritic cell indoleamine 2,3-dioxygenase (IDO) fosters the in vitro development of human iTregs via tryptophan depletion and kynurenine (Kyn) metabolites. We now show that stimulation of naïve CD4+ T cells in low tryptophan (low Trp) plus Kyn supports human iTreg generation. In vitro, low Trp + Kyn iTregs and tTregs potently suppress T effector cell proliferation equivalently but are phenotypically distinct. Compared with tTregs or T effector cells, bioenergetics profiling reveals that low Trp + Kyn iTregs have increased basal glycolysis and oxidative phosphorylation and use glutaminolysis as an energy source. Low Trp + Kyn iTreg viability was reliant on interleukin (IL)-2 in vitro. Although in vivo IL-2 administration increased low Trp + Kyn iTreg persistence on adoptive transfer into immunodeficient mice given peripheral blood mononuclear cells to induce GVHD, IL-2–supported iTregs did not improve recipient survival. We conclude that low Trp + Kyn create suppressive iTregs that have high metabolic needs that will need to be addressed before clinical translation.
Original language | English (US) |
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Pages (from-to) | 3098-3113 |
Number of pages | 16 |
Journal | American Journal of Transplantation |
Volume | 17 |
Issue number | 12 |
DOIs | |
State | Published - Dec 2017 |
Bibliographical note
Publisher Copyright:© 2017 The American Society of Transplantation and the American Society of Transplant Surgeons
Keywords
- T cell biology
- basic (laboratory) research/science
- bone marrow/hematopoietic stem cell transplantation
- graft-versus-host disease (GVHD)
- immune regulation
- immunosuppression/immune modulation
- tolerance: clinical
- translational research/science
- xenotransplantation