Innate Immunity: The Virtues of a Nonclonal System of Recognition

One of the predictions of the clonal selection theory was the ability of mature peripheral lymphocytes to discriminate between self and nonself. All self-reactive lymphocytes were thought to be deleted during maturation, and any molecule presented to the mature lymphocytes would be regarded as nonself and should therefore induce an adaptive immune response. Indeed, early experiments with model antigens, such as simple chemicals conjugated to self serum proteins and injected with adjuvants showed that responses to such antigens were the norm rather than the exception. However, if unmodified self antigens, and even nonself proteins, were administered alone in the absence of adjuvant, they gave rise to tolerance rather than an immune response. Immune responses specific even for self antigens could be induced, however, if the self antigen was mixed with adjuvants.Although adjuvants have a long history, so far they have only been defined operationally as any substance that increases the immunogenicity of admixed antigens. The reason for the failure of pure antigens to induce immune response is now known—the antigens used in these studies failed to induce the costimulatory signal necessary for the activation of lymphocytes. Accordingly, the mechanism of adjuvant activity has been proposed to be due to the induction of costimulatory signals by microbial constituents carrying PAMPs that are routinely mixed in adjuvants (Janeway 1989xCold Spring Harbor Symp. Janeway, C.A. Jr. Quant. Biol. 1989; 54: 1–13Crossref | PubMedSee all ReferencesJaneway 1989). Recognition of these PAMPs by PRRs is suggested to induce the signals necessary for lymphocyte activation (such as B7) and differentiation (effector cytokines; see above). In other words, adjuvants induce the innate immune system to produce the signals that are required for activation of an adaptive immune response. While adjuvants are potent immunostimulators, most of them cannot be used in the clinic because of unwanted side effects, and much adjuvant research has been directed toward identification of the active components of the adjuvants and their subsequent modification to minimize side effects (for review, seeAudibert and Lise 1993xAudibert, F.M. and Lise, L.D. Immunol. Today. 1993; 14: 281–284Abstract | Full Text PDF | PubMedSee all ReferencesAudibert and Lise 1993). Characterization of the nonclonal receptors of the innate immune system responsible for the adjuvant activity, and, evidently, for the associated side effects, would provide a powerful alternative approach, which would ultimately allow one to target these receptors directly. In one example of such a rational approach, fusion of an antigen with C3dg, a product of complement activation, resulted in dramatic potentiation of a specific immune response to the fused antigen (Dempsey et al 1996xDempsey, P.W., Allison, M.E., Akkaraju, S., Goodnow, C.C., and Fearon, D.T. Science. 1996; 271: 348–350Crossref | PubMedSee all ReferencesDempsey et al 1996).Rational approaches to vaccine design based on the detailed understanding of the molecular mechanisms of innate immunity should ultimately allow one not only to induce a specific adaptive immune response but also the desired effector mechanism without the accompanying damage to the host tissues.