TY - JOUR
T1 - Reprogramming of Th1 cells into regulatory T cells through rewiring of the metabolic status
AU - Kanamori, Mitsuhiro
AU - Nakatsukasa, Hiroko
AU - Ito, Minako
AU - Chikuma, Shunsuke
AU - Yoshimura, Akihiko
N1 - Funding Information:
This work was supported by JSPS KAKENHI (S) 17H06175, Advanced Research & Development Programs for Medical Innovation (AMED-CREST) JP17gm0510019 (to A.Y.), Grant-in-Aid for Young Scientists (B) (no. 16K19108 to M.K.) from the Japan Society for the Promotion of Science, the Takeda Science Foundation, the Uehara Memorial Foundation, the Kanae Foundation and the SENSHIN Medical Research Foundation, and Keio Gijuku Academic Developmental Funds (to M.K. and .S.C.).
Publisher Copyright:
© The Japanese Society for Immunology. 2018.
PY - 2018/7/24
Y1 - 2018/7/24
N2 - T helper type 1 (Th1) cells form one of the most stable CD4 T-cell subsets, and direct conversion of fully differentiated Th1 to regulatory T (Treg) cells has been poorly investigated. Here, we established a culture method for inducing Foxp3 from Th1 cells of mice and humans. This is achieved simply by resting Th1 cells without T-cell receptor ligation before stimulation in the presence of transforming growth factor-beta (TGF-ß). We named the resulting Th1-derived Foxp3+ cells Th1reg cells. Mouse Th1reg cells showed an inducible Treg-like phenotype and suppressive ability both in vitro and in vivo. Th1reg cells could also be induced from in vivo-developed mouse Th1 cells. Unexpectedly, the resting process enabled Foxp3 expression not through epigenetic changes at the locus, but through metabolic change resulting from reduced mammalian target of rapamycin complex 1 (mTORC1) activity. mTORC1 suppressed TGF-ß-induced phosphorylation of Smad2/3 in Th1 cells, which was restored in rested cells. Our study warrants future research aiming at development of immunotherapy with Th1reg cells.
AB - T helper type 1 (Th1) cells form one of the most stable CD4 T-cell subsets, and direct conversion of fully differentiated Th1 to regulatory T (Treg) cells has been poorly investigated. Here, we established a culture method for inducing Foxp3 from Th1 cells of mice and humans. This is achieved simply by resting Th1 cells without T-cell receptor ligation before stimulation in the presence of transforming growth factor-beta (TGF-ß). We named the resulting Th1-derived Foxp3+ cells Th1reg cells. Mouse Th1reg cells showed an inducible Treg-like phenotype and suppressive ability both in vitro and in vivo. Th1reg cells could also be induced from in vivo-developed mouse Th1 cells. Unexpectedly, the resting process enabled Foxp3 expression not through epigenetic changes at the locus, but through metabolic change resulting from reduced mammalian target of rapamycin complex 1 (mTORC1) activity. mTORC1 suppressed TGF-ß-induced phosphorylation of Smad2/3 in Th1 cells, which was restored in rested cells. Our study warrants future research aiming at development of immunotherapy with Th1reg cells.
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U2 - 10.1093/intimm/dxy043
DO - 10.1093/intimm/dxy043
M3 - Article
C2 - 29982622
AN - SCOPUS:85055449352
SN - 0953-8178
VL - 30
SP - 357
EP - 373
JO - International immunology
JF - International immunology
IS - 8
ER -