In Vitro Induction of Human Regulatory T Cells Using Conditions of Low Tryptophan Plus Kynurenines

K. L. Hippen, R. S. O'Connor, A. M. Lemire, A. Saha, E. A. Hanse, N. C. Tennis, S. C. Merkel, A. Kelekar, J. L. Riley, B. L. Levine, C. H. June, L. A. Turka, L. S. Kean, M. L. MacMillan, J. S. Miller, J. E. Wagner, David H Munn, B. R. Blazar

Research output: Contribution to journalArticle

9 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)3098-3113
Number of pages16
JournalAmerican Journal of Transplantation
Volume17
Issue number12
DOIs
StatePublished - Dec 1 2017

Fingerprint

Kynurenine
Regulatory T-Lymphocytes
Tryptophan
Graft vs Host Disease
Interleukin-2
Indoleamine-Pyrrole 2,3,-Dioxygenase
Adoptive Transfer
Interleukins
Oxidative Phosphorylation
Human Development
Glycolysis
In Vitro Techniques
Dendritic Cells
Energy Metabolism
Blood Cells
Cell Proliferation
T-Lymphocytes
Survival

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

ASJC Scopus subject areas

  • Immunology and Allergy
  • Transplantation
  • Pharmacology (medical)

Cite this

Hippen, K. L., O'Connor, R. S., Lemire, A. M., Saha, A., Hanse, E. A., Tennis, N. C., ... Blazar, B. R. (2017). In Vitro Induction of Human Regulatory T Cells Using Conditions of Low Tryptophan Plus Kynurenines. American Journal of Transplantation, 17(12), 3098-3113. https://doi.org/10.1111/ajt.14338

In Vitro Induction of Human Regulatory T Cells Using Conditions of Low Tryptophan Plus Kynurenines. / Hippen, K. L.; O'Connor, R. S.; Lemire, A. M.; Saha, A.; Hanse, E. A.; Tennis, N. C.; Merkel, S. C.; Kelekar, A.; Riley, J. L.; Levine, B. L.; June, C. H.; Turka, L. A.; Kean, L. S.; MacMillan, M. L.; Miller, J. S.; Wagner, J. E.; Munn, David H; Blazar, B. R.

In: American Journal of Transplantation, Vol. 17, No. 12, 01.12.2017, p. 3098-3113.

Research output: Contribution to journalArticle

Hippen, KL, O'Connor, RS, Lemire, AM, Saha, A, Hanse, EA, Tennis, NC, Merkel, SC, Kelekar, A, Riley, JL, Levine, BL, June, CH, Turka, LA, Kean, LS, MacMillan, ML, Miller, JS, Wagner, JE, Munn, DH & Blazar, BR 2017, 'In Vitro Induction of Human Regulatory T Cells Using Conditions of Low Tryptophan Plus Kynurenines', American Journal of Transplantation, vol. 17, no. 12, pp. 3098-3113. https://doi.org/10.1111/ajt.14338
Hippen, K. L. ; O'Connor, R. S. ; Lemire, A. M. ; Saha, A. ; Hanse, E. A. ; Tennis, N. C. ; Merkel, S. C. ; Kelekar, A. ; Riley, J. L. ; Levine, B. L. ; June, C. H. ; Turka, L. A. ; Kean, L. S. ; MacMillan, M. L. ; Miller, J. S. ; Wagner, J. E. ; Munn, David H ; Blazar, B. R. / In Vitro Induction of Human Regulatory T Cells Using Conditions of Low Tryptophan Plus Kynurenines. In: American Journal of Transplantation. 2017 ; Vol. 17, No. 12. pp. 3098-3113.
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AU - Hanse, E. A.

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AU - June, C. H.

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