SELECTIVE INDUCTION OF CD73 EXPRESSION IN HUMAN-LYMPHOCYTES BY CD38 LIGATION - A NOVEL PATHWAY LINKING SIGNAL TRANSDUCERS WITH ECTO-ENZYME ACTIVITIES

CD73 is a glycosyl phosphatidylinositol (CPI)-anchored purine salvage enzyme (ecto-5'-nucleotidase (ecto-5'-NT), E.C, 3.1.3.5) whose express ion on lymphocytes is dependent on their differentiation state and fun ction. CD73 behaves as an agonistic molecule in signaling via the CD3/ TCR and CD2 pathways and is associated with CTL generation, Ige produc tion, and activation of resting naive CD8(+) T cells, CD73 deficiency has been reported in a variety of patients with impaired T and/or B ce ll function. Thus, CD73 holds promise as a molecular target for interv ention in the immune system, but the mechanisms regulating its express ion are largely unknown. The aim of this study was to gain insight int o the regulation of CD73 expression in human lymphocytes. CD38, anothe r cell surface differentiation Ag with ecto-enzyme activities (NAD(+) glycohydrolase, ADP-ribosyl cyclase, and cyclic ADP-ribose (cADPR) hyd rolase), was found to specifically induce CD73 expression in T and B c ell lines as well as in normal adult T and NK cells, cord blood T cell s, and thymocytes. CD38 cross-linking induced a rapid export to the ce ll surface of pre-formed CD73 derived from an intracellular pool and n ot from de novo biosynthesis. This translocation was dependent on prot ein tyrosine kinase (PTK) activity and lasted approximately eight hour s, after which CD73 was removed from the cell surface by enzymatic cle avage. CD73 was not induced by other agents that activate T cells and CD73 was the only GPl-anchored molecule up-regulated by CD38 ligation out of six analyzed. These results document a novel pathway in human l ymphocytes leading from CD38 ligation to CD73 expression, which may re sult in the rapid acquisition of new functions, including increased pu rine salvage, increased sensitivity to Ag-induced activation, and the generation of adenosine (Ado) for Ado receptor signaling.