SummaryThe induction of tolerance in mice to preparations of deaggregated human gamma globulin (DHGG) results in in vitro antigen-specific unresponsiveness in CD4 + T cells as well as in both the T helper 1 (Thl) and Th2-1ike subpopulations. Whereas both CD45RB hi and CD45RB l~ cells from lymph nodes of HGG/complete Freund's adjuvant-immunized mice (control) proliferated in vitro to HGG, both subpopulations from mice previously tolerized with DHGG failed to respond. Furthermore, CD4 + T cells from control, but not from DHGG-injected mice, secreted high levels of interleukin 2 (IL-2) after in vitro stimulation with HGG. Although significant levels of IL-4 in supernatants of control CD4 + cells stimulated with HGG were detected in some, but not all, experiments, significant levels of IL-4 were never detected in supernatants of HGGstimulated tolerant CD4 + cells. The demonstration that serum IgG1 anti-HGG is preferentially produced in a few tolerant mice that exhibit a leaky tolerant state suggests that tolerance induction may be more dif~cult to induce in IL-4-than in IL-2-producing cells.A solid and long-lasting tolerant state can be induced in adult mice by a single injection of deaggregated human gamma globulin (DHGG) 1 (for a review see reference 1). Although tolerance is induced in both T and B cells, the dose of tolerogen required for B cell tolerance is 2-3 log10 greater than that for T cell tolerance (for a review see reference 1). The tolerant state in T cells is of long duration, whereas in B cells it is of relatively short duration (2). Induction of tolerance in T cells is independent of the thymus and is not controlled by regulating T cells (3). Although the in vivo induction of tolerance in the T cells can be interfered with by generators of IL-1 or IL-1 itself (4, 5), once induced, the tolerant state cannot be terminated by these reagents. In addition to the in vivo induction of tolerance, tolerance has been induced in HGG-specific T cell clones using either DHGG (6, 7) or inappropriate antigen presentation (8-10). Whereas tolerance in Thl clones is induced in terms of both proliferation and T cell help, tolerance in Th2 clones is induced at only the T helper level (10, 11). Whether the in vivo induction of tolerance occurs in all CD4 + cell populations has recently been questioned. Data have been reported that imply that DHGG induces tolerance in IL-2-producing T cells, but induces responsiveness in IL-4-producing cells, resulting in IL-4 production and T helper activity (12).1Abbreviations used in tkis paper: DHGG, deaggregated human gamma globulin; HGG, human gamma globulin.In this report, the susceptibility of CD4 § cells and their subsets to the induction of tolerance to DHGG was assessed. Our results demonstrate that when mice are exposed to HGG as a tolerogen before immunization, such that the in vitro antigen-specific proliferation of CD4 + T cells is totally abrogated and serum antibody levels are dramatically reduced, antigen-specific proliferation of both Thl-and Th2-1ike subsets is abroga...