Immunostimulatory activity of haptenated proteins.
Antigen recognition alone is insufficient for the activation of adaptive immune responses mediated by conventional lymphocytes. Additional signals that indicate the origin of the antigen are also required. These signals are generally provided by the innate immune system upon recognition of conserved microbial structures by a variety of pattern recognition receptors (PRRs). The Toll-like receptors (TLRs) are the best-characterized family of PRRs and control the activation of adaptive immune responses to a variety of immunizations and infections. However, recent studies have questioned the role of TLRs in the induction of antibody responses and, thus, this issue has become controversial. In contrast to earlier studies supporting a role for TLRs in antibody responses, these studies used haptenated antigens rather than native antigens for immunization, but did not consider the potential effect of antigen haptenation on immunogenicity. Here, we show that commonly used haptenated proteins, unlike native proteins, are inherently immunogenic. This immunogenicity is TLR-independent, but the T and B cell responses induced are primarily hapten-specific, rather than protein-specific. Thus, although haptens have immunostimulatory activity, it is distinct from classical adjuvants, which induce immune responses directed at the admixed antigens. Our results thus highlight an unappreciated and unique immunogenicity of haptenated proteins, and provide an experimental explanation for a seeming discrepancy between published results.
Palm
Noah W
NW
Howard Hughes Medical Institute and Department of Immunobiology, Yale University School of Medicine, 300 Cedar Street, New Haven, CT 06510, USA.
Medzhitov
Ruslan
R
D033942:Adaptor Proteins, Vesicular Transport / Q000172:deficiency / Q000276:immunology; D000536:Aluminum Hydroxide; D000818:Animals; D000941:Antigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D005620:Freund's Adjuvant / Q000276:immunology; D006241:Haptens / Q000276:immunology*; D007109:Immunity / Q000276:immunology; D007114:Immunization; D007074:Immunoglobulin G / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D051193:Toll-Like Receptors / Q000276:immunology
D033942:Adaptor Proteins, Vesicular Transport; D000536:Aluminum Hydroxide; D000941:Antigens; D005620:Freund's Adjuvant; D006241:Haptens; D007074:Immunoglobulin G; D053594:Myeloid Differentiation Factor 88; D051193:Toll-Like Receptors; C476286:Ticam1 protein, mouse