THE NATURAL IMMUNE-RESPONSE TO INHALED SOLUBLE-PROTEIN ANTIGENS INVOLVES MAJOR HISTOCOMPATIBILITY COMPLEX (MHC) CLASS-I RESTRICTED CD8-CELLMEDIATED BUT MHC CLASS-II RESTRICTED CD4+ T-CELL-DEPENDENT IMMUNE DEVIATION RESULTING IN SELECTIVE SUPPRESSION OF IMMUNOGLOBULIN-E PRODUCTION( T)

The immunological basis for atopy is currently ascribed to an inherent bias in the CD4+ T cell response to nonreplicating antigens presented at mucosal surfaces, resulting in dominance of the T helper 2 (Th2) i nterleukin 4 (IL-4)-producing phenotype, which favors IgE production. In contrast, the ''normal'' response to such antigens involves a predo minance of interferon gamma (IFN-gamma)-producing Th1 clones. This dif ference has been suggested to be the result of active selection in ato pics for Th2 (and hence against Th1) clones at the time of initial ant igen presentation. In the study below, we demonstrate that the natural immune response to inhaled protein antigens, particularly in animals expressing the low immunoglobulin E (IgE) responder phenotype, include s a major histocompatibility complex (MHC) class I-restricted CD8+ T c ell component, the appearance of which is associated with active suppr ession of IgE antibody production. Thus, continued exposure of rats to aerosolized ovalbumin (OVA) antigen elicits a transient IgE response, that is terminated by the onset of a state of apparent ''tolerance'' to further challenge, and this tolerant state is transferable to naive animals with CD8+ T cells. Kinetic studies on in vitro T cell reactiv ity in these aerosol-exposed rats demonstrated biphasic CD4+ Th2 respo nses which terminated, together with IgE antibody production, and coin cident with the appearance of MHC class I-restricted OVA-specific IFN- gamma-producing CD8+ T cells. However, the latter were not autonomous in vitro and required a source of exogenous IL-2 for initial activatio n, which in CD8+-enriched splenocyte cultures could be provided by sma ll numbers of contaminating OVA-specific CD4+ T cells. This represents the first formal evidence for the induction of an MHC class I-restric ted T cell response to natural mucosal exposure to an inert protein an tigen, and is consistent with a growing literature demonstrating sensi tization of MHC class I-restricted CD8+ T cells by deliberate immuniza tion with soluble proteins. We suggest that crossregulation of MHC cla ss II-restricted CD4+ T cells via cytokine signals generated in parall el CD8+ T cell responses represents a covert and potentially important selection pressure that can shape the nature of host responses to non replicating antigens presented at mucosal surfaces.