Alterations in cellular metabolism modulate CD1d-mediated NKT-cell responses.
Natural killer T (NKT) cells play a critical role in the host's innate immune response. CD1d-mediated presentation of glycolipid antigens to NKT cells has been established; however, the mechanisms by which NKT cells recognize infected or cancerous cells remain unclear. 5(')-AMP activated protein kinase (AMPK) is a master regulator of lipogenic pathways. We hypothesized that activation of AMPK during infection and malignancy could alter the repertoire of antigens presented by CD1d and serve as a danger signal to NKT cells. In this study, we examined the effect of alterations in metabolism on CD1d-mediated antigen presentation to NKT cells and found that an infection with lymphocytic choriomeningitis virus rapidly increased CD1d-mediated antigen presentation. Hypoxia inducible factors (HIF) enhance T-cell effector functions during infection, therefore antigen presenting cells pretreated with pharmacological agents that inhibit glycolysis, induce HIF and activate AMPK were assessed for their ability to induce NKT-cell responses. Pretreatment with 2-deoxyglucose, cobalt chloride, AICAR and metformin significantly enhanced CD1d-mediated NKT-cell activation. In addition, NKT cells preferentially respond to malignant B cells and B-cell lymphomas express HIF-1α. These data suggest that targeting cellular metabolism may serve as a novel means of inducing innate immune responses.
Department of Microbiology and Immunology, University of Maryland School of Medicine and the Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD 21201, USA twebb@som.umaryland.edu.
Tonya J
TJ
Webb
Department of Microbiology and Immunology, University of Maryland School of Medicine and the Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD 21201, USA.
Gregory B
GB
Carey
Department of Microbiology and Immunology, University of Maryland School of Medicine and the Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD 21201, USA.
James E
JE
East
Department of Microbiology and Immunology, University of Maryland School of Medicine and the Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD 21201, USA.
Wenji
W
Sun
Department of Microbiology and Immunology, University of Maryland School of Medicine and the Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD 21201, USA.
Dominique R
DR
Bollino
Department of Microbiology and Immunology, University of Maryland School of Medicine and the Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD 21201, USA.
Amy S
AS
Kimball
Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Randy R
RR
Brutkiewicz
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D055610:Antigens, CD1d / Q000378:metabolism*; D002460:Cell Line; D004195:Disease Models, Animal; D004734:Energy Metabolism; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D056747:Immunomodulation; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D055611:Natural Killer T-Cells / Q000276:immunology* / Q000378:metabolism*; D009369:Neoplasms / Q000276:immunology / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D014777:Virus Diseases / Q000276:immunology / Q000378:metabolism / Q000821:virology
D055610:Antigens, CD1d; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D055372:AMP-Activated Protein Kinases
CD1d; LCMV; NKT cells; antigen processing; metabolism