Bone marrow cells inhibit the generation of autologous EBV-specific CTL.
Recently, we reported that human bone marrow cells (BMC) inhibited the proliferative (recall) response of lymphocytes to Epstein-Barr virus (EBV) and cytomegalovirus (CMV) protein antigens [12]. To clarify further the effect of BMC on the immune response to viral antigens, we obtained PBL from EBV IgG antibody positive kidney transplant recipients (R) and their living-related donors (LRD) 1 year after renal transplantation and generated EBV-specific CTL in vitro in the presence or absence of autologous BMC. The addition of freshly aspirated autologous iliac crest BMC from either R or LRD caused a significant inhibitory effect on the generation of EBV-specific CTL from CTL precursors, in contrast to the addition of autologous PBL used as controls (62.29 +/- 10.85% inhibition using BMC from the kidney transplant recipients; 74.47 +/- 15.21% inhibition using BMC from the living-related donors). This inhibitory effect was only exerted during the CTL generation phase; but not in the effector CTL killing phase. The expression of CD94, a component of the killer inhibitory receptor (KIR) on CD3(+) cells was elevated in the cultures with BMC, in contrast to the cultures without BMC. The BMC inhibitory effect was partially abrogated by pre-incubation of the CTL effectors with anti-CD94 monoclonal antibody, in contrast with its isotype control. In addition, supernatants obtained from the CTL generating cultures with BMC contained high levels of prostaglandin E(2) (PGE(2)), and EBV-specific CTL activity was inhibited by the addition of exogenous PGE(2) in the absence of BMC. The induction of CD40L cell surface expression by anti-CD3 was also decreased on the effector T cell population when BMC were added. There was a concomitant reduction in protein kinase C (PKC) activity. These studies demonstrate that BMC exert an inhibitory effect on T cell-mediated immunity to viral antigens in humans by regulating autologous effector T cell generation and early T cell activation signaling pathways.
Jin
Y
Y
Division of Transplantation, Department of Surgery, University of Miami, Florida, USA.
Fuller
L
L
Esquenazi
V
V
Blomberg
B B
BB
Rosen
A
A
Tzakis
A G
AG
Ricordi
C
C
Miller
J
J
D015703:Antigens, CD / Q000032:analysis; D001854:Bone Marrow Cells / Q000276:immunology*; D016026:Bone Marrow Transplantation / Q000276:immunology*; D017252:CD3 Complex / Q000032:analysis; D019013:CD40 Antigens / Q000032:analysis; D002461:Cell Line, Transformed / Q000276:immunology* / Q000821:virology; D015536:Down-Regulation; D005434:Flow Cytometry; D004854:Herpesvirus 4, Human / Q000276:immunology; D006801:Humans; D007111:Immunity, Cellular; D037181:Lectins, C-Type; D007963:Leukocytes, Mononuclear; D008562:Membrane Glycoproteins / Q000032:analysis; D051920:NK Cell Lectin-Like Receptor Subfamily D; D011458:Prostaglandins E / Q000032:analysis / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism; D018183:Transplantation Chimera / Q000187:drug effects / Q000276:immunology*
D015703:Antigens, CD; D017252:CD3 Complex; D019013:CD40 Antigens; C497869:KLRD1 protein, human; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins; D051920:NK Cell Lectin-Like Receptor Subfamily D; D011458:Prostaglandins E; D011494:Protein Kinases