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In Vitro Induction of Human Regulatory T Cells Using Conditions of Low Tryptophan Plus Kynurenines
Author(s) -
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 D. H.,
Blazar B. R.
Publication year - 2017
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/ajt.14338
Subject(s) - medicine , in vitro , tryptophan , biochemistry , biology , amino acid
Thymic regulatory T cells ( tT regs) and induced regulatory T cells ( iT regs) 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 iT regs via tryptophan depletion and kynurenine (Kyn) metabolites. We now show that stimulation of naïve CD 4 + T cells in low tryptophan (low Trp) plus Kyn supports human iT reg generation. In vitro , low Trp + Kyn iT regs and tT regs potently suppress T effector cell proliferation equivalently but are phenotypically distinct. Compared with tT regs or T effector cells, bioenergetics profiling reveals that low Trp + Kyn iT regs have increased basal glycolysis and oxidative phosphorylation and use glutaminolysis as an energy source. Low Trp + Kyn iT reg viability was reliant on interleukin (IL) ‐2 in vitro . Although in vivo IL ‐2 administration increased low Trp + Kyn iT reg persistence on adoptive transfer into immunodeficient mice given peripheral blood mononuclear cells to induce GVHD , IL ‐2–supported iT regs did not improve recipient survival. We conclude that low Trp + Kyn create suppressive iT regs that have high metabolic needs that will need to be addressed before clinical translation.