SECONDARY IGE RESPONSES IN-VIVO ARE PREDOMINANTLY GENERATED VIA GAMMA(1)EPSILON-DOUBLE POSITIVE B-CELLS

We have recently developed a model in which mice were treated with IL- 4 after primary immunization, resulting in elevated total serum IgG(1) and IgE levels, but decreased antigen-specific levels and memory form ation for these isotypes. In this report, we describe that these effec ts of IL-4 are mediated at the B cell and not the T-cell level. Major changes occurred in the gamma(1) epsilon-double positive B-cell popula tion which is increased as a result of IL-4 treatment. Moreover, it is shown that gamma(1) epsilon-double positive B cells can develop in vi tro out of gamma(1) epsilon-positive primed B cells and that these dou ble positive cells can differentiate into IgG(1)- and IgE-secreting ce lls. The existence of gamma(1) epsilon-double positive memory B cells can explain the differences in cytokine dependence of TNP-specific mem ory IgG(1) and IgE responses found after adoptively transferring prime d spleen cells into irradiated naive recipients. Whereas the IL-4 inde pendent TNP-specific memory IgG(1) responses could be blocked efficien tly by neutralizing IL-5 and IL-6, TNP-specific memory IgE responses w ere virtually not susceptible to such treatment. These IgE responses w ere also not susceptible to IFN-gamma, used in doses that could inhibi t the primary IgE response. Inhibition of the TNP-specific memory IgG( 1) response by neutralizing IL-5 and IL-6 is accompanied by a 10-fold increase of the IL-4 independent TNP-specific IgE memory response. The se data indicate that secondary IgE responses primarily result from B cells that are either switched to IgG(1), or are double positive for I gG(1) and IgE, thereby suggesting a minor role for E-single positive B cells in secondary IgE responses.