Primary MHC-Class II+ Cells Are Necessary To Promote Resting Vδ2 Cell Expansion in Response to ( E )-4-Hydroxy-3-Methyl-But-2-Enyl-Pyrophosphate and Isopentenyl Pyrophosphate

Abstract

Human Vγ9δ2 (Vδ2) T cells represent a unique effector T cell population in humans and primates detecting nonpeptid phosphoantigens, playing an important role in antimicrobial and antitumor immunity. Currently, it is believed that various leukocyte subsets can promote phosphoantigen-driven Vδ2 cell expansion, but the essential cell type required remains elusive. We have used high purity cell sorting to analyze the cellular requirements for (E)-4-hydroxy-3-methyl-but-2-enyl-pyrophosphate (HMBPP)–driven Vδ2 cell expansion. To our knowledge, we show for the first time that primary human MHC-class II+ cells are indispensable for HMBPP- and isopentenylpyrophosphate-driven Vδ2 cell expansion. In contrast, MHC-class II− cells are unable to promote Vδ2 cell expansion. Moreover, purified primary human TCRαβ+ T cells, CD4+, or CD8+ T cells also failed to promote HMBPP-mediated Vδ2 expansion. Depletion of CD4+CD25+ T cells demonstrated that inability of TCRαβ+ cells to expand Vδ2 cells was not related to the presence of regulatory T cells. Separation of MHC-class II+ cells into dendritic cells, monocytes, and B cells revealed that dendritic cells were the most potent Vδ2 expanders. Pulsing experiments demonstrated that HMBPP transforms MHC-class II+ but not negative cells into Vδ2 expanders. MHC-class II–blocking experiments with mAbs and secondary MHC-class II induction on CD4+ T cells after CD3/CD28 costimulation indicated that MHC-class II is necessary, but not sufficient to promote Vδ2 expansion. Our results provide novel insight into the primary cell-specific requirements for human Vδ2 expansion.