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J Immunol. 2018 Jan 15;200(2):643-656. doi: 10.4049/jimmunol.1602110. Epub 2017 Dec 13.

Early Inhibition of Fatty Acid Synthesis Reduces Generation of Memory Precursor Effector T Cells in Chronic Infection.

Author information

1
Division of Infectious Diseases, Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555.
2
Biomedical Informatics, Institute for Translational Science, University of Texas Medical Branch, Galveston, TX 77555.
3
Department of Anesthesiology, University of Texas Medical Branch, Galveston, TX 77555.
4
Shriners Hospital for Children, Galveston, TX 77550.
5
Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030.
6
Division of Endocrinology, University of Texas Medical Branch, Galveston, TX 77555; and.
7
Division of Infectious Diseases, Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555; rostephe@utmb.edu.
8
Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555.

Abstract

Understanding the mechanisms of CD4 memory T cell (Tmem) differentiation in malaria is critical for vaccine development. However, the metabolic regulation of CD4 Tmem differentiation is not clear, particularly in persistent infections. In this study, we investigated the role of fatty acid synthesis (FAS) in Tmem development in Plasmodium chabaudi chronic mouse malaria infection. We show that T cell-specific deletion and early pharmaceutical inhibition of acetyl CoA carboxylase 1, the rate limiting step of FAS, inhibit generation of early memory precursor effector T cells (MPEC). To compare the role of FAS during early differentiation or survival of Tmem in chronic infection, a specific inhibitor of acetyl CoA carboxylase 1, 5-(tetradecyloxy)-2-furoic acid, was administered at different times postinfection. Strikingly, the number of Tmem was only reduced when FAS was inhibited during T cell priming and not during the Tmem survival phase. FAS inhibition during priming increased effector T cell (Teff) proliferation and strongly decreased peak parasitemia, which is consistent with improved Teff function. Conversely, MPEC were decreased, in a T cell-intrinsic manner, upon early FAS inhibition in chronic, but not acute, infection. Early cure of infection also increased mitochondrial volume in Tmem compared with Teff, supporting previous reports in acute infection. We demonstrate that the MPEC-specific effect was due to the higher fatty acid content and synthesis in MPEC compared with terminally differentiated Teff. In conclusion, FAS in CD4 T cells regulates the early divergence of Tmem from Teff in chronic infection.

PMID:
29237780
PMCID:
PMC5760294
DOI:
10.4049/jimmunol.1602110
[Indexed for MEDLINE]
Free PMC Article

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