A regulatory cross-talk between Vγ9Vδ2 T lymphocytes and mesenchymal stem cells

The physiological functions of human TCRV gamma 9V delta 2(+) gamma delta lymphocytes reactive to non-peptide phosphoantigens contribute to cancer immunosurveillance and immunotherapy. However, their regulation by mesenchymal stem cells (MSC), multipotent and immunomodulatory progenitor cells able to infiltrate tumors, has not been investigated so far. By analyzing freshly isolated TCRV gamma 9V delta 2(+) lymphocytes and primary cell lines stimulated with synthetic phosphoantigen or B-cell lymphoma cell lines in the presence of MSC, we demonstrated that MSC were potent suppressors of gamma delta-cell proliferation, cytokine production and cytolytic responses in vitro. This inhibition was mediated by the COX-2-dependent production of prostaglandin E2 (PGE(2)) and by MSC through EP2 and EP4 inhibitory receptors expressed by V gamma 9V delta 2 T lymphocytes. COX-2 expression and PGE(2) production by MSC were not constitutive, but were induced by IFN-gamma and TNF-alpha secreted by activated V gamma 9V delta 2 T cells. This regulatory cross-talk between MSC and Vy9V82 T lymphocytes involving PGE2 could be of importance for the antitumor and antimicrobial activities of gamma delta T cells.