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

Akanni Adededji Abdoul Ibitokou, Brian E. Dillon, Mala Sinha, Bartosz Szczesny, Añahi Delgadillo, Doaa Reda Abdelrahman, Csaba Szabo, Lutfi Abu-Elheiga, Craig Porter, Demidmaa Tuvdendorj, Robin Stephens

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5 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)643-656
Number of pages14
JournalJournal of Immunology
Volume200
Issue number2
DOIs
StatePublished - Jan 15 2018

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ASJC Scopus subject areas

  • Immunology

Cite this

Ibitokou, A. A. A., Dillon, B. E., Sinha, M., Szczesny, B., Delgadillo, A., Abdelrahman, D. R., Szabo, C., Abu-Elheiga, L., Porter, C., Tuvdendorj, D., & Stephens, R. (2018). Early Inhibition of Fatty Acid Synthesis Reduces Generation of Memory Precursor Effector T Cells in Chronic Infection. Journal of Immunology, 200(2), 643-656. https://doi.org/10.4049/jimmunol.1602110