Transcriptomics,Genomics

Dataset Information

61

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


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, but not during the Tmem survival phase. FAS inhibition during priming increased effector T cells (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 to 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 to terminally differentiated Teff. In conclusion, FAS in CD4 T cells regulates the early divergence of Tmem from Teff in chronic infection. Overall design: B5 TCR Tg mice were infected with P. chabaudi. Effector and memory T cells subsets were sorted at day 8 and d60 post infection respectively. Naïve T cells from uninfected mice were sorted as well. Gene expression was measured in three effector subsets, three memory subsets and and naive T cells. Two replicates were performed using different donors for each experiment.

INSTRUMENT(S): Agilent-028005 SurePrint G3 Mouse GE 8x60K Microarray (Probe Name version)

SUBMITTER: Robin Stephens 

PROVIDER: GSE89555 | GEO | 2016-11-05

SECONDARY ACCESSION(S): PRJNA352552

REPOSITORIES: GEO

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

Ibitokou Samad A SA   Dillon Brian E BE   Sinha Mala M   Szczesny Bartosz B   Delgadillo Añahi A   Reda Abdelrahman Doaa D   Szabo Csaba C   Abu-Elheiga Lutfi L   Porter Craig C   Tuvdendorj Demidmaa D   Stephens Robin R  

Journal of immunology (Baltimore, Md. : 1950) 20171213 2


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 limiti  ...[more]

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