A soluble survival signal from CD14+ cells and its possible role in the pathogenesis of rheumatoid arthritis

Abstract

Since macrophages play an important role in T cell activation, we investigated the role of CD14+ cells in T cell activation, proliferation and activation-induced cell death (AICD). Using PHA for activation, it was found that CD14+ cell depletion resulted in significantly greater AICD, decreased lymphocyte growth and increased IL-2 secretion. Lymphocyte activation was delayed as defined by CD69 and CD25 expression. ³H-TdR-incorporation was reduced in proportion to the percentage of AICD in the cultures. Addition of supernatants from activated CD14+ cells to CD14+ cell-depleted mononuclear cell cultures reversed the effects on AICD, IL-2 secretion and lymphocyte growth. Supernatants from TNF-α matured dendritic cells demonstrated the same activity as the CD14 cocktails. These data suggested a soluble survival signal from CD14+ cells that prevented apoptosis, maintaining an active immune response. Further studies demonstrated that depletion of CD14+ cells in rheumatoid arthritis (RA) patients resulted in greater AICD, decreased lymphocyte proliferation and even higher secretion of IL-2 compared with normal control subjects. While the CD14+ cell percentage in RA was not significantly higher than that in the age/sex-matched healthy controls, CD14 supernatants from RA showed a significantly greater protective effect on AICD. Data analysis revealed that CD14 supernatants supported the survival of activated lymphocytes in RA. These data underscored the importance of the soluble survival signal in the homeostasis of the immune system and in the pathogenesis of RA. The analysis of apoptotic cells showed that most of the apoptotic cells bore activation antigen CD69 and T cell antigen CD3, suggesting that most of the apoptotic cells were activated T lymphocytes. The soluble signal was also investigated. The CD14 cocktails contain IL-1β, TNF-α, TGF-β and IL-6, but not IL-12, or IL-15. Depletion assays using a panning method followed by blocking of residual IL-1β and TNF-α with corresponding monoclonal antibodies had no effect on the active AICD protection. As TGF-β was found in the culture medium containing 10% FBS, TGF-β might not be an active factor in the CD14 cocktails. Because the CD14 cocktails did not contain IL-12 or IL-15, these two cytokines were not the active factors either.