Journal
PATHOGENS AND DISEASE
Volume 74, Issue 6, Pages -Publisher
OXFORD UNIV PRESS
DOI: 10.1093/femspd/ftw055
Keywords
CD1d; NKT cells; metabolism; antigen processing; LCMV
Categories
Funding
- National Institutes of Health [R21 CA162277, R21 CA199544, R21 CA184469, R01 46455]
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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-1 alpha. These data suggest that targeting cellular metabolism may serve as a novel means of inducing innate immune responses.
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