IN-VIVO TOLERANCE INDUCTION AND ASSOCIATED CYTOKINE PRODUCTION BY SUBSETS OF MURINE CD4(-CELLS() T)

Male BXSB mice develop lupus-like disease and die early in life (4 to 5 mo) whereas female mice do not. Others have demonstrated that CD4(+) cells from male mice support B cell resistance to tolerance induction to human gamma-globulin (HGG). In this study, male and female mice to lerized at 2 mo of age with deaggregated HGG and subsequently immunize d with HGG in comparison with mice immunized only were tested for anti -HGG Ab responses. CD4(+) cells from draining lymph nodes of these mic e were tested in culture for proliferation and production of cytokine mRNA and protein in response to HGG plus APC. Tolerized male but not f emale mice produced anti-HGG Abs of both the IgG1 and IgG2a isotypes. HGG-stimulated CD4(+) cells from immunized male and female mice that w ere not tolerized produced IL-2, IL-4, IL-5, IFN-gamma, and TNF-beta m RNA as well as IL-2 and IL-4 protein, whereas tolerized, immunized mic e of both sexes failed to proliferate or produce either IL-2 or IL-4 o r express any cytokine mRNA in response to HGG in vitro. A resistance in tolerance induction in male mice, as determined by anti-HGG Abs, wa s also observed at 3 mo of age. Although a resistance to tolerance was also seen in terms of proliferation in the 3-mo-old males, production of IL-2 or IL-4 protein was still not observed. Thus, all T cell subs ets identified by cytokine expression profiles were tolerized not only from females but also from males, of which the latter appeared to sho w some resistance to tolerance induction.