Enhanced development of Th2-like primary CD4 effectors in response to sustained exposure to limited rIL-4 in vivo

Previous studies have established that cytokines regulate development of Th cell subsets from naive CD4 cells, suggesting promising therapeutic potential for cytokines that has not been fully realized, in part due to high dose toxicity. Here we examined effects of sustained delivery of low doses of rIL-4 on development of cytokine-secreting primary CD4 cells in vivo. Diffusion chambers injected with X63.Ag-653 plasmacytoma transfectants that constitutively produce rIL-4 were implanted s.c. in mice 24 to 48 h before immunization with keyhole limpet hemocyanin (KLH). Five days later at the peak of the response, KLH-specific CD4 cells from controls, which received chambers containing untransfected plasmacytoma cells, secreted primarily IL-2 and IL-4, with low levels of IFN-gamma and no IL-5 following Ag restimulation. Administration of rIL-4 enhanced IL-2 and IL-4 production by two- to fivefold, with a corresponding decrease in IFN-gamma. As frequencies of KLH-specific precursors that secreted IL-4 were unaltered, exogenous cytokine apparently affected the magnitude of IL-4 secretion by primed CD4 cells. Although IL-4 was undetectable in sera of mice carrying chambers, titers of KLH-specific IgG1 and IgG3 Ab were increased by rIL-4, whereas IgM, IgG2a, and IgG2b levels were unaltered. The results indicate that sustained delivery of low doses of cytokines at sites distant from Ag exposure can selectively potentiate development of CD4 subsets.