ReviewControl of adaptive immune responses by Toll-like receptors
Introduction
Adaptive immune responses are initiated when T cells recognize foreign peptides bound to self-MHC molecules expressed on antigen-presenting cells (APCs). Over the years we have learned that T cell activation requires not only recognition of a foreign-peptide–MHC complex but also the expression of costimulatory molecules such as CD80 and CD86 on APCs. Consequently, expression of costimulatory molecules must be tightly regulated. Until recently this regulation was not well understood. Over a decade ago, Janeway hypothesized that regulation of costimulation must be controlled by receptors with specificity for microbial products, thereby linking innate recognition of non-self with induction of adaptive immunity [1]. The function of the recently identified Toll-like receptor (TLR) family appears to fit with this hypothesis, and recent evidence suggests that TLRs play an important role in controlling adaptive immune responses.
TLRs are evolutionarily conserved, germline encoded receptors that recognize specific molecular patterns associated with microbes. There are currently 10 known TLR family members and the number of known TLR ligands continues to grow. In many cases these ligands represent unique products of microbial metabolism, such as lipopolysaccharide (LPS) and peptidoglycan. Other ligands are highly conserved features of a particular class of microbe, such as hypomethylated CpG DNA motifs [2••], dsRNA [3••] or bacterial flagellin [4••]. Collectively, all these ligands have been termed pathogen-associated molecular patterns (PAMPs). Recognition of PAMPs by TLRs initiates a signaling pathway that leads to activation of NF-κB transcription factors and members of the MAP kinase family [5]. TLRs share a common intracellular domain that is similar to that of IL-1 receptors and therefore called the Toll/IL-1-receptor (TIR) domain. All TLRs signal through a TIR-domain-containing adaptor, MyD88. Mice lacking MyD88 are deficient in TLR signaling and generally do not respond to TLR ligands [6].
TLRs are expressed primarily on macrophages and dendritic cells (DCs) and control the activation of these APCs [5]. In DCs, TLR signaling triggers a maturation program that includes upregulation of MHC and costimulatory molecules and expression of pro-inflammatory cytokines such as TNFα, IL-1 and IL-6. This maturation of DCs significantly increases their ability to prime naı̈ve T cells. In this way, TLRs link the recognition of pathogens with induction of adaptive immune responses. An important focus of recent research has been to understand whether this link between innate and adaptive immunity can affect what type of adaptive immune response is mounted. This review will discuss the role that TLRs play in the induction of adaptive immune responses.
Section snippets
TLRs and induction of adaptive immunity
DCs occupy a central position in the immune system as the cells responsible for priming of naı̈ve T cells [7]. Priming of CD4 T cells is a critical event in the induction of an adaptive response, because the differentiation of these cells determines the nature of the adaptive response [8]. In response to viruses, intracellular pathogens and various bacteria, CD4 T cells differentiate into Th1 cells. This differentiation is dependent on the production of IL-12 by DCs. Th1 cells produce IFNγ and
Recognition of Type 2 pathogens
As discussed above, the ability of the TLR family to discriminate between different classes of pathogens does not appear to control Type 2 immune responses directly. Instead, the multicellular parasites and allergens that induce Type 2 responses may be recognized through a different system. Understanding the molecular basis of this recognition is essential if we hope to understand how innate recognition controls adaptive immune responses.
In general, the innate immune system uses two strategies
Conclusions
There is accumulating evidence that molecular recognition of pathogens by cells of the innate immune system is responsible for determining the nature of the adaptive immune response. Bacteria, viruses and other microbes are identified as non-self through recognition of PAMPs by the TLR family. The ensuing response involves activation of a signaling pathway in DCs that leads to upregulation of MHC and costimulatory molecules and the expression of NF-κB dependent genes such as IL-1, IL-6, TNFα
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
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