INTERLEUKIN-4 PRODUCTION BY CD4(-CELLS FROM ALLERGIC INDIVIDUALS IS MODULATED BY ANTIGEN CONCENTRATION AND ANTIGEN-PRESENTING CELL-TYPE() T)

We have previously shown that CD4+ T cells from allergic individuals a re predisposed to produce interleukin (IL)-4 in response to allergens, and that allergen immunotherapy greatly reduced IL-4 production in an allergen-specific fashion. The mechanism that results in the reductio n of IL-4 synthesis in treated individuals is unknown, but because cli nical improvement during immunotherapy is associated with the administ ration of the highest doses of allergen, we hypothesized that high con centration of allergen results in the downregulation of IL-4 synthesis in CD4+ T cells. In this report, we demonstrated that CD4+ T cells fr om allergic donors produced high levels of IL-4 when stimulated with l ow concentrations of allergen (0.003-0.01 mu g/ml), particularly when B cell-enriched populations presented the antigen. In contrast, the sa me responding CD4+ T cell population produced little IL-4 when stimula ted with high concentrations of allergen (10-30 mu g/ml), especially w hen monocytes were used as antigen-presenting cells (APC). The quantit y of IL-4 produced was also found to be inversely related to the exten t of proliferation of the CD4+ T cells in response to allergen/antigen ; maximal proliferation of CD4+ T cells occurred in response to high c oncentrations of antigen when IL-4 production was minimal. Antigen pre sentation by B cell-enriched populations, instead of monocytes, induce d less CD4+ T cell proliferation, but induced much greater IL-4 synthe sis. Moreover, the addition of increasing numbers of APC (either B cel ls or monocytes) to cultures containing a constant number of responder T cells resulted in increased T cell proliferation and decreased IL-4 production. These results indicate that the circumstances under which memory T cells are activated, as well as the strength of the prolifer ative signal to T cells, greatly affect the quantity of IL-4 produced. Thus, our observations that the cytokine profile of allergen-specific memory CD4+ T cells can indeed be modulated by the antigen dose and A PC type suggest that methods that preferentially enhance allergen upta ke by monocytes and that enhance T cell proliferation will improve the clinical efficacy of immunotherapy in the treatment of allergic disea se.