Enhanced Fatty Acid Synthesis Leads to Subset Imbalance and IFN-γ Overproduction in T Helper 1 Cells

• Published in: Frontiers in immunology Vol. 11; p. 593103
• Main Authors: Iwata, Shigeru, Zhang, Mingzeng, Hao, He, Trimova, Gulzhan, Hajime, Maiko, Miyazaki, Yusuke, Ohkubo, Naoaki, Satoh Kanda, Yurie, Todoroki, Yasuyuki, Miyata, Hiroko, Ueno, Masanobu, Nagayasu, Atsushi, Nakayamada, Shingo, Sakata, Kei, Tanaka, Yoshiya
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 30-11-2020
• Subjects: fatty acid synthesis; IFN-γ; Immunology; immunometabolism; systemic lupus erythematosus; T-bet; IFN-γ; systemic lupus erythematosus; fatty acid synthesis; immunometabolism; T-bet
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2020.593103

Recent reports have shown the importance of IFN-γ and T-bet
B cells in the pathology of SLE, suggesting the involvement of IFN-γ-producing T-bet
CD4
cells, i.e., Th1 cells. This study determined the changes in Th1 subsets with metabolic shift and their potential as therapeutic targets in SLE. Compared with healthy donors, patients with SLE had higher numbers of T-bet
CXCR3
effector cells and T-bet
Foxp3
non-suppressive cells, which excessively produce IFN-γ, and lower number of non-IFN-γ-producing T-bet
Foxp3
activated-T
cells. These changes were considered to be involved in treatment resistance. The differentiation mechanism of Th1 subsets was investigated
using memory CD4
cells obtained from healthy donors and patients with SLE. In memory CD4
cells of healthy donors, both rapamycin and 2-deoxy-D-glucose (2DG) suppressed T-bet
Foxp3
cells, and induced T-bet
Foxp3
cells. Rapamycin induced IFN-γ-producing T-bet
Foxp3
cells accompanied with enhanced lipid metabolism, whereas 2DG induced IFN-γ-non-producing T-bet
Foxp3
cells. In memory CD4
cells of SLE patients, inhibition of fatty acid synthesis, but not β-oxidation, suppressed IFN-γ production, and up-regulated of Foxp3 expression in T-bet
Foxp3
cells. Metabolic regulators such as fatty acid synthesis inhibitors may improve the pathological status by correcting Th1 subset imbalance and overproduction of IFN-γ in SLE.