Preferential recognition of a microbial metabolite by human Vgamma2Vdelta2 T cells.
Human Vgamma2Vdelta2 T cells are stimulated by prenyl pyrophosphates, such as isopentenyl pyrophosphate (IPP), and play important roles in mediating immunity against microbial pathogens and have potent anti-tumor activity. (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP) has been identified as a metabolite in the 2-C-methyl-D-erythritol-4 phosphate (MEP) pathway for isoprenoid biosynthesis that is used by many bacteria and protozoan parasites. We find that HMBPP is the major Vgamma2Vdelta2 T-cell antigen for many bacteria, including Mycobacterium tuberculosis, Yersinia enterocolitica and Escherichia coli. HMBPP was a 30 000-fold more potent antigen than IPP. Using mutant bacteria, we show that bacterial antigen levels for Vgamma2Vdelta2 T cells are controlled by MEP pathway enzymes and find no evidence for the production of 3-formyl-1-butyl pyrophosphate. Moreover, HMBPP reactivity required only germ line-encoded Vgamma2Vdelta2 TCR elements and is present at birth. Importantly, we show that bacterial HMBPP levels correlated with their ability to expand Vgamma2Vdelta2 T cells in vivo upon engraftment into severe combined immunodeficiency-beige mice. Thus, the production of HMBPP by a microbial-specific isoprenoid pathway plays a major role in determining whether bacteria will stimulate Vgamma2Vdelta2 T cells in vivo. This preferential stimulation by a common microbial isoprenoid metabolite allows Vgamma2Vdelta2 T cells to respond to a broad array of pathogens using this pathway.
Puan
Kia-Joo
KJ
Division of Rheumatology, Department of Internal Medicine and the Interdisciplinary Graduate Program in Immunology, University of Iowa College of Medicine, EMRB 400F, Iowa City, IA 52242, USA.
Jin
Chenggang
C
Wang
Hong
H
Sarikonda
Ghanashyam
G
Raker
Amy M
AM
Lee
Hoi K
HK
Samuelson
Megan I
MI
Märker-Hermann
Elisabeth
E
Pasa-Tolic
Ljiljana
L
Nieves
Edward
E
Giner
José-Luis
JL
Kuzuyama
Tomohisa
T
Morita
Craig T
CT
D000818:Animals; D011756:Diphosphates / Q000138:chemical synthesis / Q000276:immunology / Q000302:isolation & purification* / Q000378:metabolism*; D045782:Hemiterpenes / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D023421:Models, Animal; D015394:Molecular Structure; D020102:Mycobacterium smegmatis / Q000737:chemistry / Q000276:immunology; D009943:Organophosphorus Compounds / Q000737:chemistry / Q000378:metabolism; D011106:Polyisoprenyl Phosphates / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology
C443995:4-hydroxy-3-methylbut-2-enyl pyrophosphate; D011756:Diphosphates; D045782:Hemiterpenes; D009943:Organophosphorus Compounds; D011106:Polyisoprenyl Phosphates; D016692:Receptors, Antigen, T-Cell, gamma-delta; C004809:isopentenyl pyrophosphate