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Immunostimulatory Activity of Haptenated Proteins

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Immunostimulatory Activity of Haptenated Proteins Immunostimulatory activity of haptenated proteins Noah W. Palm and Ruslan Medzhitov1 Howard Hughes Medical Institute and Department of Immunobiology, Yale University School of Medicine, 300 Cedar Street, New Haven, CT 06510 Communicated by Richard A. Flavell, Yale University School of Medicine, New Haven, CT, September 30, 2008 (received for review July 15, 2008) Antigen recognition alone is insufficient for the activation of In previous studies, we investigated the role of the TLR adaptive immune responses mediated by conventional lympho- signaling pathway in the induction of adaptive immune re- cytes. Additional signals that indicate the origin of the antigen are sponses, using mice deficient in the critical TLR signaling also required. These signals are generally provided by the innate adaptor Myeloid Differentiation primary response gene 88 immune system upon recognition of conserved microbial struc- (MyD88) (9, 10). To isolate the contribution of TLRs we used a tures by a variety of pattern recognition receptors (PRRs). The single defined TLR ligand, Lipopolysaccharide (LPS), as an Toll-like receptors (TLRs) are the best-characterized family of PRRs adjuvant, and the native proteins ovalbumin (OVA) or human and control the activation of adaptive immune responses to a serum albumin (HSA), as model antigens. incomplete Freund’s variety of immunizations and infections. However, recent studies adjuvant (IFA) and aluminum hydroxide, which contain low have questioned the role of TLRs in the induction of antibody levels of contaminating PRR ligands, were used simply for their responses and, thus, this issue has become controversial. In con- depot effect, which is important for soluble antigens. Using this ϩ trast to earlier studies supporting a role for TLRs in antibody system, we demonstrated that optimal CD4 T cell responses and responses, these studies used haptenated antigens rather than T-dependent antibody responses require intact TLR signaling; native antigens for immunization, but did not consider the poten- furthermore, we showed that optimal T-dependent antibody tial effect of antigen haptenation on immunogenicity. Here, we responses to OVA and HSA not only require TLR signaling in show that commonly used haptenated proteins, unlike native the antigen presenting dendritic cells, but also depend on TLR proteins, are inherently immunogenic. This immunogenicity is signaling in B cells (10). Notably, the contribution of TLRs to TLR-independent, but the T and B cell responses induced are antibody responses depended on the antibody isotype and was primarily hapten-specific, rather than protein-specific. Thus, al- restricted to IgM, IgG1 and IgG2 classes, whereas the IgE though haptens have immunostimulatory activity, it is distinct response was not dependent on TLRs (10, 11). The role of a B from classical adjuvants, which induce immune responses directed cell intrinsic TLR signal in antibody production was also dem- at the admixed antigens. Our results thus highlight an unappreci- onstrated in the human system (12) and in the murine system in ated and unique immunogenicity of haptenated proteins, and response to viral infection (13, 14) or virus-like particles (15), provide an experimental explanation for a seeming discrepancy and in autoimmunity (16–18). between published results. Despite a large body of evidence linking TLRs and adaptive immunity, 2 recent reports have questioned the role of TLRs in adjuvant ͉ antibody ͉ innate immunity ͉ Toll-like receptor antibody production based on analysis of antibody responses in MyD88 and TRIF (TIR-domain-containing adapter-inducing ␤ nnate immune recognition is mediated by several families of IFN- ) double-deficient mice or mice with a B cell-specific Ipattern recognition receptors (PRRs), including the Toll-like deficiency in MyD88 (19–21). The reasons for this discrepancy receptors (TLRs), NOD-like receptors (NLRs), Dectin-1 and are not clear, creating considerable confusion with regard to the involvement of TLRs in the control of antibody responses. related C-type lectin receptors, and retinoic acid inducible Studies producing conflicting data on the role of TLRs in gene-I (RIG-I) and melanoma differentiation-associated gene-5 antibody responses differ notably in the type of antigen used for (MDA-5) (1). Each family of PRRs is specialized to deal with immunization. Although studies supporting a role for TLRs (9, particular classes of pathogens. For example, Dectin-1 detects 10) used unmodified native protein antigens, studies that failed the fungal cell wall component ␤-glucan (2) and induces phago- to find such a role (19–21) used antigens that were chemically cytosis and activation of the T helper-17 (Th17) arm of adaptive modified by haptenation—a procedure involving the conjugation immunity (3, 4). Nucleotide-binding oligomerization domain of multiple small chemical moieties to a carrier protein. Hap- containing 1 (NOD1) and NOD2 proteins detect peptidoglycan tenation is a widely used approach to study antibody responses. fragments in the cytosol and contribute to both innate and Antibody responses to haptenated proteins are T cell dependent adaptive responses (5). RIG-I and MDA-5 recognize viral RNA (22) and, thus, protein haptenation is thought to simply provide and trigger IFN production and antiviral immunity, including defined epitopes for the measurement of antibody titers and activation of cytotoxic T lymphocytes (CTLs) (6, 7). TLRs detect affinities without altering the requirements for B cell responses. a variety of molecular structures derived from bacterial, viral and However, we show here that certain haptenated proteins are fungal pathogens and lead to the activation of T and B cells (8). highly immunogenic, whereas native proteins are nonimmuno- Each of these families of PRRs is capable of activating the genic. Unlike native proteins mixed with adjuvant, which induced appropriate class of the adaptive immune response. Therefore, strong anti-protein responses, haptenated proteins induced strong the combination of immunostimulatory components (i.e., PRR hapten-specific responses, but weak protein-specific responses. This ligands) contained in a given pathogen determines the relative unique immunogenicity was TLR-independent, and CD4ϩ T cell requirement for any particular PRR in activation of adaptive and IgG1 responses to haptenated antigens were therefore largely immunity. Most pathogens contain ligands for more than 1 MyD88-independent. Haptenated proteins therefore possess a family of PRRs, which complicates analyses of the roles of different PRR families. However, analysis of the specific mech- anisms of activation of the adaptive immune response can be Author contributions: N.W.P. and R.M. designed research; N.W.P. performed research; facilitated by the use of model antigens and simple adjuvants, N.W.P. and R.M. analyzed data; and N.W.P. and R.M. wrote the paper. whereby targeting of a particular class of PRRs, using their The authors declare no conflict of interest. corresponding microbial ligands, provides an adjuvant activity 1To whom correspondence should be addressed. E-mail: [email protected]. and confers immunogenicity to otherwise nonimmunogenic This article contains supporting information online at www.pnas.org/cgi/content/full/ protein antigens. 0809403105/DCSupplemental. 4782–4787 ͉ PNAS ͉ March 24, 2009 ͉ vol. 106 ͉ no. 12 www.pnas.org͞cgi͞doi͞10.1073͞pnas.0809403105 Downloaded by guest on September 24, 2021 HSA+LPS Alum DNP(29)-HSA Alum ABOVA+LPS IFA DNP(7)-OVA+LPS IFA HSA+LPS IFA DNP(29)-HSA IFA 40 60 125 15 75 150 g/ml) g/ml) g/ml) g/ml) 100 g/ml) g/ml) µ µ µ µ 45 µ µ 30 50 75 100 30 10 50 20 25 50 15 25 5 IgG1 Anti-DNP ( IgG1 Anti-HSA ( IgG1 Anti-OVA ( IgG1 Anti-OVA 0 IgG1 Anti-DNP ( 0 0 0 10 WT MyD88-/- WT MyD88-/- WT MyD88-/- WT MyD88-/- 7.5 10 7.5 IgG1 Anti-HSA ( 2.0 IgG1 Anti-DNP ( g/ml) 0 0 g/ml) g/ml) g/ml) µ µ µ µ 7.5 WT MyD88-/- WT MyD88-/- 5.0 1.5 5.0 5.0 1.0 Fig. 2. Haptenated proteins in aluminum hydroxide adjuvant induce robust 2.5 2.5 2.5 0.5 IgG1 responses in MyD88-deficient mice. WT C57BL/6 and MyD88-deficient IgG2c Anti-HSA ( IgG2c Anti-OVA ( IgG2c Anti-OVA IgG2c Anti-DNP ( 0 IgG2c Anti-DNP ( 0 0 0 mice were immunized i.p. with either HSA plus LPS or DNP(29)-HSA in alum. WT MyD88-/- WT MyD88-/- WT MyD88-/- WT MyD88-/- Serum HSA- or DNP-specific IgG1 was measured on day 14 after immunization Fig. 1. Haptenated proteins in IFA induce robust IgG1 responses in MyD88- by ELISA. deficient mice. Age matched MyD88-deficient and WT C57BL/6 mice were immunized in the footpad with OVA or DNP(7)-OVA plus LPS (A) or with low ؉ endotoxin HSA plus LPS or DNP(29)-HSA (B) emulsified in IFA. HSA-, OVA- or Haptenated Proteins Induce MyD88-Independent CD4 T Cell Re- DNP-specific serum antibody titers were measured by ELISA on day 14 after sponses. Antibody responses can be characterized as either immunization. T-dependent or T-independent based on the requirement for T cell help. Highly multivalent antigens and antigens that specif- ically induce innate immune pathways in B cells can induce unique, hapten-focused immunogenicity that affects the require- T-independent antibody responses. However, antibody re- ments for adaptive immune activation. Thus, studies questioning sponses to native proteins and haptenated proteins alike are T the role of TLRs in antibody responses reached their conclusions cell-dependent (22). We have shown previously that T cell because of the unappreciated effects of protein haptenation on responses to native antigen plus LPS emulsified in IFA are immunogenicity. This created a controversy in the field regarding TLR-dependent (refs. 9 and 24 and Fig. 3). We wished to the role of TLRs in antibody responses. Our data reconfirm the ϩ examine whether CD4 T cell responses to haptenated antigens importance of TLRs in antibody responses to native proteins plus are also TLR-signaling dependent.
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