The Interleukin-2-mTORc1 Kinase Axis Defines the Signaling, Differentiation, and Metabolism of T Helper 1 and Follicular B Helper T Cells

John P Ray; Matthew M Staron; Justin A Shyer; Ping-Chih Ho; Heather D Marshall; Simon M Gray; Brian J Laidlaw; Koichi Araki; Rafi Ahmed; Susan M Kaech; Joe Craft

doi:10.1016/j.immuni.2015.08.017

The Interleukin-2-mTORc1 Kinase Axis Defines the Signaling, Differentiation, and Metabolism of T Helper 1 and Follicular B Helper T Cells

Immunity. 2015 Oct 20;43(4):690-702. doi: 10.1016/j.immuni.2015.08.017. Epub 2015 Sep 22.

Authors

Affiliations

¹ Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
² Emory Vaccine Center and Department of Microbiology and Immunology, Atlanta, GA 30322, USA.
³ 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.
⁴ 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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis
Calcium Signaling
Cell Cycle
Cell Division
Enzyme Activation
Glucose / metabolism
Glycolysis
Interleukin-2 / physiology*
Interleukin-2 Receptor alpha Subunit / physiology
Lymphocytic choriomeningitis virus / immunology
Mechanistic Target of Rapamycin Complex 1
Mice, Inbred C57BL
Multiprotein Complexes / physiology*
NFATC Transcription Factors / physiology
Oxygen Consumption
Positive Regulatory Domain I-Binding Factor 1
Proto-Oncogene Proteins c-akt / physiology*
Signal Transduction / physiology*
Specific Pathogen-Free Organisms
T-Lymphocyte Subsets / cytology
T-Lymphocyte Subsets / immunology
T-Lymphocyte Subsets / metabolism*
T-Lymphocytes, Helper-Inducer / cytology
T-Lymphocytes, Helper-Inducer / immunology
T-Lymphocytes, Helper-Inducer / metabolism*
T-Lymphocytes, Helper-Inducer / virology
TOR Serine-Threonine Kinases / physiology*
Th1 Cells / cytology
Th1 Cells / immunology
Th1 Cells / metabolism
Transcription Factors / biosynthesis
Transcription Factors / genetics

Substances

Il2ra protein, mouse
Interleukin-2
Interleukin-2 Receptor alpha Subunit
Multiprotein Complexes
NFATC Transcription Factors
Prdm1 protein, mouse
Transcription Factors
Positive Regulatory Domain I-Binding Factor 1
Akt1 protein, mouse
Mechanistic Target of Rapamycin Complex 1
Proto-Oncogene Proteins c-akt
TOR Serine-Threonine Kinases
Glucose

Associated data

GEO/GSE55596

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding