Pattern recognition receptors in innate immunity, host defense, and immunopathology

Abstract

Infection by pathogenic microbes initiates a set of complex interactions between the pathogen and the host mediated by pattern recognition receptors. Innate immune responses play direct roles in host defense during the early stages of infection, and they also exert a profound influence on the generation of the adaptive immune responses that ensue. An improved understanding of the pattern recognition receptors that mediate innate responses and their downstream effects after receptor ligation has the potential to lead to new ways to improve vaccines and prevent autoimmunity. This review focuses on the control of innate immune activation and the role that innate immune receptors play in helping to maintain tissue homeostasis.

Keywords: Toll-like receptors; antigen presentation; chemokines; damage-associated molecular patterns; pathogen-associated molecular patterns; pattern recognition receptors; vaccines.

Fig. 1.

The Toll-like receptor (TLR) signaling pathway. TLR ligation leads to the activation of NF-κB and MAPKs. Myeloid differentiation primary response gene 88 (MyD88), a key TLR adapter protein, associates with IL-1 receptor-associated kinase (IRAK)4, which, in turn, phosphorylates IRAK1. After its interaction with TNF receptor-associated factor (TRAF)6, the activated IRAK complex phosphorylates transforming growth factor-β-activated kinase 1/MAP3K-binding protein 1 (TAB1) and TGF-β-activated kinase-1, which activate NF-κB and MAPK pathways. MD-2, myeloid differentiation protein-2; IKK, IκB kinase. [Reprinted with permission from Ref. .]

Fig. 2.

Vaccination against Mycobacterium tuberculosis. Immunization with M. tuberculosis antigen ID93 along with TLR4 agonist glucopyranosyl lipid adjuvant (GLA) induced protective immunity. Guinea pigs were injected with saline or were immunized with bacille Calmette-Guerin (BCG) as a positive control, ID93/SE (stable oil in water emulsion adjuvant without GLA), or ID93/GLA-SE. The survival of guinea pigs after M. tuberculosis infection was measured up to day 210. Saline-injected and ID93/SE-immunized guinea pigs succumbed to M. tuberculosis infection, whereas those immunized with BCG or ID93/GLA-SE survived. [Reprinted with permission from Ref. .]

Fig. 3.

TLRs and allergy. Neonatal (3 days old) and adult (6 wk old) A/Sn mice were immunized with antigen from the dust mite Blomia tropicalis (Bt), Bt + CpG oligodeoxynucleotide (ODN), or control ODN. Total IgE concentrations were determined by ELISA. The reduction of serum IgE concentrations in mice immunized with antigen and TLR9 agonist shows the potential of immune-modulatory strategies to cure allergies. [Reprinted with permission from Ref. .]

Fig. 4.

Nanoparticle (NP)-based vaccinations. CD8⁺ T cell proliferation and activation was determined after incubation of mouse bone marrow dendritic cells and OT-1 T cells with various concentrations of OVA within NPs harboring OVA and TLR ligands (TLRLs) (NP-DEC205-OVA-TLRL or NP-Isotype-OVA-TLRL, respectively) or within NPs harboring only OVA (NP-DEC205-OVA or NP-Isotype-OVA, respectively). After 3 days, CD8⁺ T cell activation was determined by measuring interferon (IFN)-γ levels in supernatants. Targeted delivery of antigen and TLRL via NPs resulted in higher amounts of IFN-γ production. [Reprinted with permission from Ref. .]