Aberrant CD3- and CD28-Mediated Signaling Events in Cord Blood T Cells Are Associated with Dysfunctional Regulation of Fas Ligand-Mediated Cytotoxicity

Abstract

AbstractThere have been numerous reports of decreased acute and chronic graft-vs-host disease (GVHD) in patients receiving HLA-matched or HLA-disparate umbilical cord transplants. However, little is known about the mechanisms underlying the low incidence of GVHD in umbilical cord blood transplantation (CBT). In this study, we examined CD3- and CD28-mediated functional properties and signaling events in CB T cells (CBTCs). Dual stimulation of peripheral blood TCs (PBTCs) and bone marrow TCs (BMTCs) with mAbs to CD3- and CD28-induced expressions of Fas ligand (FasL), as well as CD25 and CD154 (CD40L), whereas defective induction of these activation-associated cell surface molecules were observed in CBTCs. Engagement of both CD3 and CD28 induced FasL-mediated cytotoxicity in peripheral blood TCs (PBTCs) but not CBTCs; however, both of these tissue sources possess intrinsically similar proliferative responsiveness. Analysis of CD3- and CD28-induced signal transduction revealed a deficiency in signaling events that involved repressed tyrosine phosphorylation and enzymatic activities of a family of mitogen-activated protein kinases, extracellular signal-regulated kinase 2, stress-activated protein kinase/c-jun N-terminal kinase (SAPK/JNK), and p38mapk, as well as p56lck and ZAP-70 in CBTCs compared with those in PBTCs. These results suggest that CD3- and CD28-mediated signaling events blockage in CBTCs may be responsible for dysfunction of FasL-mediated cytotoxicity and lead to the low incidence of severe GVHD in CBT.