Titanium uptake, induction of RANK‐L expression, and enhanced proliferation of human T‐lymphocytes

There is increasing evidence that titanium ions are released from orthopedic implants by biocorrosion. The aim of this study was to investigate titanium uptake by human T‐lymphocytes and its effects on phenotype and proliferation. Freshly isolated human nonadherent peripheral blood mononuclear cells (NA‐PBMC), were exposed to TiCl₄ [Ti(IV)]. Bioavailability and distribution of Ti(IV) in T‐lymphocytes was determined by energy‐filtered electron microscopy (EFTEM). The effects of Ti(IV) challenge on nonactivated and PHA‐activated cells were assessed by flow cytometric analysis of surface markers, RANK‐L production, and proliferation assays. EFTEM colocalized Ti(IV) with phosphorus in the nucleus, ribosomes, cytoplasmic membranes, and the surface membrane of T‐lymphocytes. Ti(IV) increased significantly the expression of CD69, CCR4, and RANK‐L in a concentration‐dependent manner. Titanium enters T‐lymphocytes through a currently unknown mechanism and binds to phosphorus‐rich cell structures. Titanium influences phenotype and function of T‐lymphocytes, resulting in activation of a CD69+ and CCR4+ T‐lymphocyte population and secretion of RANK‐L. These results strongly suggest the involvement of titanium ions challenged T‐lymphocytes in the complex pathophysiological mechanisms of aseptic loosening of orthopedic implants.