A role for the mevalonate pathway in the induction of subtype cross-reactive immunity to influenza A virus by human gammadelta T lymphocytes.
The major gammadelta T cell subset in the human peripheral blood expresses the Vgamma9delta2 TCR and recognizes non-peptidic prenyl pyrophosphate antigens such as isopentylpyrophosphate (IPP). Upon activation the gammadelta T cells rapidly secrete antiviral cytokines similar to classical memory alphabeta T cells. Here we have investigated the ability of gammadelta T lymphocytes from human PBMC to become activated by influenza A virus infection. Vgamma9Vdelta2 T lymphocytes rapidly upregulate expression of CD25 and CD69 and produce IFN-gamma following influenza infection of PBMC. Moreover, the recognition is cross-reactive between various subtypes of influenza, but not with vaccinia virus. Vgamma9Vdelta2 T cell responses are potently reduced by the HMG-CoA reductase inhibitor mevastatin, which inhibits the mevalonate pathway and IPP synthesis. Our results indicate that influenza virus infection induces the rapid activation and function of Vgamma9Vdelta2 T lymphocytes in the peripheral blood via a mechanism that depends on the mevalonate pathway.
Jameson
Julie M
JM
The Scripps Research Institute, 10550 North Torrey Pines Rd., La Jolla, CA 92037, USA. jamesonj@scripps.edu
Cruz
John
J
Costanzo
Anne
A
Terajima
Masanori
M
Ennis
Francis A
FA
D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis / Q000235:genetics; D000956:Antigens, Viral / Q000276:immunology / Q000378:metabolism; D003429:Cross Reactions; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007211:Indoles / Q000276:immunology / Q000378:metabolism; D009980:Influenza A virus / Q000276:immunology* / Q000472:pathogenicity; D007251:Influenza, Human / Q000276:immunology* / Q000378:metabolism; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis / Q000235:genetics; D037181:Lectins, C-Type / Q000096:biosynthesis / Q000235:genetics; D008148:Lovastatin / Q000031:analogs & derivatives* / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D008798:Mevalonic Acid / Q000378:metabolism; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000096:biosynthesis; D013045:Species Specificity; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000821:virology; D000099192:CD69 Antigens
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D000956:Antigens, Viral; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D007371:Interferon-gamma; D053645:Interleukin-2 Receptor alpha Subunit; D037181:Lectins, C-Type; D008148:Lovastatin; D008798:Mevalonic Acid; D016692:Receptors, Antigen, T-Cell, gamma-delta; D000099192:CD69 Antigens; C521523:T-cell receptor Vdelta2, human; C521522:T-cell receptor Vgamma9, human; C012258:mevastatin; C041272:indolepropanol phosphate