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

Human V gamma 9 delta 2 (V delta 2) 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 V delta 2 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 V delta 2 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 V delta 2 cell expansion. In contrast, MHC-class II- cells are unable to promote V delta 2 cell expansion. Moreover, purified primary human TCR alpha beta(+) T cells, CD4(+), or CD8(+) T cells also failed to promote HMBPP-mediated V delta 2 expansion. Depletion of CD4(+)CD25(+) T cells demonstrated that inability of TCR alpha beta(+) cells to expand V delta 2 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 V delta 2 expanders. Pulsing experiments demonstrated that HMBPP transforms MHC-class II+ but not negative cells into V delta 2 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 V delta 2 expansion. Our results provide novel insight into the primary cell-specific requirements for human V delta 2 expansion. The Journal of Immunology, 2012, 189: 5212-5222.