title: The Interleukin-2-mTORc1 Kinase Axis Defines the Signaling, Differentiation, and Metabolism of T Helper 1 and Follicular B Helper T Cells.
abstract: The differentiation of CD4(+) helper T cell subsets with diverse effector functions is accompanied by changes in metabolism required to meet their bioenergetic demands. We find that follicular B helper T (Tfh) cells exhibited less proliferation, glycolysis, and mitochondrial respiration, accompanied by reduced mTOR kinase activity compared to T helper 1 (Th1) cells in response to acute viral infection. IL-2-mediated activation of the Akt kinase and mTORc1 signaling was both necessary and sufficient to shift differentiation away from Tfh cells, instead promoting that of Th1 cells. These findings were not the result of generalized signaling attenuation in Tfh cells, because they retained the ability to flux calcium and activate NFAT-transcription-factor-dependent cytokine production. These data identify the interleukin-2 (IL-2)-mTORc1 axis as a critical orchestrator of the reciprocal balance between Tfh and Th1 cell fates and their respective metabolic activities after acute viral infection.
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Ray
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Staron
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Justin A
authors.initials: JA
authors.lastname: Shyer
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Ping-Chih
authors.initials: PC
authors.lastname: Ho
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Heather D
authors.initials: HD
authors.lastname: Marshall
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Simon M
authors.initials: SM
authors.lastname: Gray
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Laidlaw
authors.affiliation: Emory Vaccine Center and Department of Microbiology and Immunology, Atlanta, GA 30322, USA.
authors.forename: Koichi
authors.initials: K
authors.lastname: Araki
authors.affiliation: Emory Vaccine Center and Department of Microbiology and Immunology, Atlanta, GA 30322, USA.
authors.forename: Rafi
authors.initials: R
authors.lastname: Ahmed
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA; Howard Hughes Medical Institute, 4000 Jones Bridge Road, Chevy Chase, MD 20815-6789, USA. Electronic address: susan.kaech@yale.edu.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Kaech
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Medicine (Rheumatology), Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: joseph.craft@yale.edu.
authors.forename: Joe
authors.initials: J
authors.lastname: Craft
mesh_terms: D000818:Animals; D017209:Apoptosis; D020013:Calcium Signaling; D002453:Cell Cycle; D002455:Cell Division; D004789:Enzyme Activation; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis; D007376:Interleukin-2 / Q000502:physiology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000502:physiology; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D000076222:Mechanistic Target of Rapamycin Complex 1; D008810:Mice, Inbred C57BL; D046912:Multiprotein Complexes / Q000502:physiology*; D050778:NFATC Transcription Factors / Q000502:physiology; D010101:Oxygen Consumption; D000074462:Positive Regulatory Domain I-Binding Factor 1; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013047:Specific Pathogen-Free Organisms; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D058570:TOR Serine-Threonine Kinases / Q000502:physiology*; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics
chemical_list: C508018:Il2ra protein, mouse; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D046912:Multiprotein Complexes; D050778:NFATC Transcription Factors; C513258:Prdm1 protein, mouse; D014157:Transcription Factors; D000074462:Positive Regulatory Domain I-Binding Factor 1; C514862:Akt1 protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D005947:Glucose