The unresponsiveness of aged mice to polysaccharide antigens is a result of a defect in macrophage function

A reduction in macrophage (M Phi) function with aging makes mice less responsive to bacterial capsular polysaccharides, such as those present in the pneumococcal polysaccharide vaccine, a model of thymus independent (TI) antigen (Ag). Using trinitrophenol (TNP)-lipopolysaccharide (LPS) and TNP-Ficoll, two other well-studied TI Ag, we studied the mechanistic basis of reduced M Phi function in the aged. We show that aged mice are profoundly hyporesponsive to these TI Ag. As a result of a requirement for M Phi, highly purified B cells from young-adult mice do not respond to TI Ag. When purified, young B cells were immunized with TNP-Ficoll, the antibody production from those cultures reconstituted with M Phi from aged mice was significantly lower than that seen with young M Phi. Consequently, this unresponsiveness can be overcome by a mixture of interleukin (IL)-I beta and IL-6. Upon stimulation with LPS, in comparison with young M Phi, aged M Phi secreted reduced amounts of IL-6, tumor necrosis factor alpha, IL-1 beta, and IL-12, cytokines necessary for B cells to respond to TI Ag. LPS also induced aged M(D to produce an excess of IL-10. Neutralization of IL-10 enhanced the production of proinflamatory cylokines by M Phi upon LPS stimulation and also induced Ab production by aged splenocytes. Thus, the inability of aged M(D to help the B cell response appears to be caused by an excess of IL-10. As aged M(D have a reduced number of cells expressing Toll-like receptor 4 and CD14, the imbalance in cytokine production might be partly a result of fewer cells expressing key components of the LPS receptor complex.