HMBPP Analog Prodrugs Bypass Energy-Dependent Uptake To Promote Efficient BTN3A1-Mediated Malignant Cell Lysis by Vγ9Vδ2 T Lymphocyte Effectors.
Vγ9Vδ2 effector T cells lyse cells in response to phosphorus-containing small molecules, providing primates a unique route to remove infected or malignant cells. Yet, the triggering mechanisms remain ill defined. We examined lysis mediated by human Vγ9Vδ2 effector T cells in response to the naturally occurring (E)-4-hydroxy-3-methyl-but-2-enyl diphosphate (HMBPP) or a synthetic cell-permeable prodrug, bis (pivaloyloxymethyl) (E)-4-hydroxy-3-methyl-but-2-enyl phosphonate. CD27(+)/CD45RA(-) Th1-like effector cells killed K562 target cells through a mechanism that could be enhanced by either compound or TCR Ab and blocked by Src inhibition or butyrophilin 3 isoform A1 (BTN3A1) disruption. Pretreatment at 4 °: C decreased HMBPP-induced lysis but did not reduce lysis induced by bis (pivaloyloxymethyl) (E)-4-hydroxy-3-methyl-but-2-enyl phosphonate. Together, our results show that internalization of HMBPP into target cells is required for BTN3A1-dependent lysis by Vγ9Vδ2 effector T cells. The enhanced activity of the prodrug analog is due to its ability to bypass the pathways required for entry of HMBPP. These findings support an inside-out model of T cell triggering driven by small-molecule induction of BTN3A1.
Department of Physiology and Neurobiology, University of Connecticut, Storrs, CT 06269;
Ashley M
AM
Kilcollins
Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269; and.
Jin
J
Li
Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269; and.
Chia-Hung Christine
CH
Hsiao
Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269; and Institute for Systems Genomics, University of Connecticut, Storrs, CT 06269 andrew.wiemer@uconn.edu.
Andrew J
AJ
Wiemer
D015703:Antigens, CD / Q000276:immunology*; D000071797:Butyrophilins / Q000276:immunology*; D003602:Cytotoxicity, Immunologic / Q000187:drug effects / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007150:Immunohistochemistry; D008213:Lymphocyte Activation / Q000187:drug effects; D010755:Organophosphates / Q000276:immunology / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D011355:Prodrugs / Q000494:pharmacology*; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*
C467061:4-hydroxy-3-methyl-2-butenyl diphosphate; D015703:Antigens, CD; C558381:BTN3A1 protein, human; D000071797:Butyrophilins; D010755:Organophosphates; D011355:Prodrugs