Bone marrow cells promote TH2 polarization and inhibit virus-specific CTL generation

Area of Science:

• Immunology
• Cell Biology
• Transplantation Science

Background:

• Human bone marrow cells (BMC) were previously shown to inhibit virus-specific cytotoxic T lymphocytes (CTL) generation in culture.
• Culture supernatants containing prostaglandin E(2) (PGE(2)) were associated with T-helper 2 (TH2) cell development and inhibition of EBV-CTL effector cells.

Purpose of the Study:

• To investigate the mechanism by which autologous BMC inhibit Epstein-Barr virus (EBV)-specific CTL generation in kidney transplant recipients.
• To determine the role of soluble factors and cell-cell contact in BMC-mediated inhibition of EBV-CTL.

Main Methods:

• Peripheral blood lymphocytes (PBL) from EBV-seropositive kidney transplant recipients and donors were stimulated with autologous EBV-transformed B cells (EBV-B) +/- autologous BMC.
• Intracellular cytokine expression (IL-4, -5, -6, -10, -13), TH2-associated receptor CCR3, Protein Kinase A (PKA), and STAT-6 phosphorylation were analyzed.
• Trans-well experiments were used to assess the role of cell-cell contact and soluble factors in BMC-mediated inhibition.

Main Results:

• Addition of BMC increased intracellular IL-4, -5, -6, -10, and -13 expression and CCR3 in CD3+ cells.
• BMC-mediated inhibition of EBV-CTL generation occurred even when BMC were separated from PBL + EBV-B by a trans-well membrane, indicating soluble factor involvement.
• BMC enhanced PKA activity and STAT-6 phosphorylation, key components of TH2-mediated signaling pathways.

Conclusions:

• Autologous BMC inhibit EBV-specific CTL generation through soluble factors, promoting TH2 cell polarization.
• TH2 cells induced by BMC directly inhibit EBV-CTL generation, with enhanced TH2-associated PKA, CCR3, and STAT-6 phosphorylation.
• Cell-cell contact is not required for BMC-mediated inhibition in this autologous system.