Differentiation, phenotype, and function of interleukin-17-producing human Vγ9Vδ2 T cells

In healthy adults, the major peripheral blood gamma delta T-cell subset expresses the V gamma 9V delta 2 TCR and displays pleiotropic features. Here we report that coculture of naive V gamma 9V delta 2 T cells with phosphoantigens and a cocktail of cytokines (IL-1-beta, TGF-beta, IL-6, and IL-23), leads to selective expression of the transcription factor ROR gamma t and polarization toward IL-17 production. IL-17(+) V gamma 9V delta 2 T cells express the chemokine receptor CCR6 and produce IL-17 but neither IL-22 nor IFN-gamma; they have a predominant terminally differentiated (CD27(-)CD45RA(+)) phenotype and express granzyme B, TRAIL, FasL, and CD161. On antigen activation, IL-17(+) V gamma 9V delta 2 T cells rapidly induce CXCL8-mediated migration and phagocytosis of neutrophils and IL-17-dependent production of beta-defensin by epithelial cells, indicating that they may be involved in host immune responses against infectious microorganisms. Accordingly, an increased percentage of IL-17(+) V gamma 9V delta 2 lymphocytes is detected in the peripheral blood and at the site of disease in children with bacterial meningitis, and this pattern was reversed after successful antibacterial therapy. Most notably, the phenotype of IL-17(+) V gamma 9V delta 2 T cells in children with meningitis matches that of in vitro differentiated IL-17(+) V gamma 9V delta 2 T cells. Our findings delineate a previously unknown subset of human IL-17(+) V gamma 9V delta 2 T lymphocytes implicated in the pathophysiology of inflammatory responses during bacterial infections. (Blood. 2011;118(1):129-138)