Ecto-ATPase CD39 Inactivates Isoprenoid-Derived Vγ9Vδ2 T Cell Phosphoantigens
Georg Gruenbacher,
Hubert Gander,
Andrea Rahm,
Marco Idzko,
Oliver Nussbaumer,
Martin Thurnher
Affiliations
Georg Gruenbacher
Immunotherapy Unit, Department of Urology, Medical University of Innsbruck and K1 Center Oncotyrol—Center for Personalized Cancer Medicine, 6020 Innsbruck, Austria
Hubert Gander
Immunotherapy Unit, Department of Urology, Medical University of Innsbruck and K1 Center Oncotyrol—Center for Personalized Cancer Medicine, 6020 Innsbruck, Austria
Andrea Rahm
Immunotherapy Unit, Department of Urology, Medical University of Innsbruck and K1 Center Oncotyrol—Center for Personalized Cancer Medicine, 6020 Innsbruck, Austria
Marco Idzko
Department of Pulmonary Medicine, University Medical Center Freiburg, 79106 Freiburg, Germany
Oliver Nussbaumer
Peter Gorer Department of Immunobiology, King’s College London, London SE1 9RT, UK
Martin Thurnher
Immunotherapy Unit, Department of Urology, Medical University of Innsbruck and K1 Center Oncotyrol—Center for Personalized Cancer Medicine, 6020 Innsbruck, Austria
In humans, Vγ9Vδ2 T cells respond to self and pathogen-associated, diphosphate-containing isoprenoids, also known as phosphoantigens (pAgs). However, activation and homeostasis of Vγ9Vδ2 T cells remain incompletely understood. Here, we show that pAgs induced expression of the ecto-ATPase CD39, which, however, not only hydrolyzed ATP but also abrogated the γδ T cell receptor (TCR) agonistic activity of self and microbial pAgs (C5 to C15). Only mevalonate-derived geranylgeranyl diphosphate (GGPP, C20) resisted CD39-mediated hydrolysis and acted as a regulator of CD39 expression and activity. GGPP enhanced macrophage differentiation in response to the tissue stress cytokine interleukin-15. In addition, GGPP-imprinted macrophage-like cells displayed increased capacity to produce IL-1β as well as the chemokine CCL2 and preferentially activated CD161-expressing CD4+ T cells in an innate-like manner. Our studies reveal a previously unrecognized immunoregulatory function of CD39 and highlight a particular role of GGPP among pAgs.
