Trends in Immunology
Volume 22, Issue 2, 1 February 2001, Pages 78-83
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Opinion
Dendritic-cell function in Toll-like receptor- and MyD88-knockout mice

https://doi.org/10.1016/S1471-4906(00)01811-1Get rights and content

Abstract

Based on recent findings in myeloid differentiation factor 88 (MyD88)- and Toll-like receptor (TLR)-knockout mice, Tsuneyasu Kaisho and Shizuo Akira discuss the roles of TLRs and MyD88 in dendritic cell (DC) maturation and cytokine production. Lipopolysaccharide binds TLR4 and can induce DC maturation in the absence of MyD88, whereas CpG DNA binds TLR9 and induces DC maturation in a MyD88-dependent manner.

Section snippets

From Drosophila Toll to the mammalian TLR family

The TLR family consists of phylogenetically conserved transmembrane proteins that are essential for innate immunity. Drosophila Toll is involved not only in dorsoventral patterning but also in host defense against fungal infection 7. Human TLR4, the mammalian homolog of Toll, was first identified by Janeway's group 8. To date, more than ten members have been reported to belong to the TLR family in mammals (8., 9., 10. and the EMBL/GenBank/DDBJ databases). Accumulating evidence suggests that

MyD88 in IL-1R and TLR signaling

The adaptor protein, myeloid differentiation factor 88 (MyD88), which possesses a TIR domain, associates with IL-1R family members and with TLRs (Fig. 1b). MyD88–TLR interactions occur via homophilic interaction of the TIR domains 14. Biological responses to IL-1 and IL-18 were completely abolished in MyD88-deficient mice 15, indicating that MyD88 is essential for IL-1–IL-18 signaling. In fact, neither IL-1 nor IL-18 can induce nuclear factor-κB (NF-κB) and mitogen-activated protein kinase

LPS can induce DC maturation in the absence of MyD88

To clarify the biological significance of this MyD88-independent pathway, the effects of LPS on DCs from MyD88-deficient mice were analyzed. Immature DCs can be cultured in vitro from bone marrow (BM) cells stimulated with granulocyte–macrophage colony-stimulating factor (GM-CSF). LPS can provoke cytokine production from wild-type BM DCs (Table 1). However, cytokine release induced by LPS stimulation was completely abolished not only in TLR4- but also in MyD88-deficient BM DCs. This is

LPS cannot induce maturation of C3H/HeJ-derived DCs

The LPS-unresponsive mouse strain C3H/HeJ carries a point mutation in the TLR4 gene locus 18., 19.. This mutation converts the 712th amino acid, a proline residue, to a histidine residue in the intracytoplasmic domain of murine TLR4 (Fig. 2). This proline residue is well conserved not only among species but also among the TLR family, with the exception of TLR3. This mutation can abolish LPS-induced cytokine responses. To assess whether this mutation affects the MyD88-independent pathway, the

The MyD88-independent pathway

MyD88 associates not only with TLR4 through the TIR domain but also with a serine threonine kinase, IL-1 receptor-associated kinase (IRAK) (Fig. 1b and Fig. 3a). Interaction of MyD88 with IRAK is mediated by homophilic interaction of their death domains and induces IRAK activation. Subsequently, IRAK stimulates NF-κB and MAPK cascades via TNF receptor-associated factor (TRAF) 6. Are the same molecules in this pathway involved in the MyD88-independent pathway?

LPS-induced IRAK activation is

CpG DNA-induced DC maturation is dependent on MyD88

Bacterial DNAs can stimulate macrophages and DCs to release cytokines and upregulate costimulatory molecules, thus inducing Th1 immune responses 22., 23., 24.. This immunostimulatory effect depends on unmethylated CpG motifs. This motif is under-represented and mostly methylated in eukaryotic DNAs that lack immunostimulatory activity. Cytokine release induced by bacterial DNAs containing CpG motifs (CpG DNA) is dependent on MyD88 and TRAF6 in macrophages 25, suggesting that the receptor for CpG

NF-κB activation and DC maturation

In TLR4 signaling, the MyD88-dependent pathway is essential for cytokine induction, whereas the MyD88-independent pathway can lead to DC maturation (Fig. 3a). Considering that C3H/HeJ DCs did not respond to LPS, the MyD88-dependent and -independent pathways must originate at the intracytoplasmic region of TLR4 and bifurcate. However, the MyD88-independent pathway can induce activation of NF-κB and MAPK cascades in the absence of MyD88 (17), whereas LPS-stimulated C3H/HeJ DCs and CpG

TLR3 does not possess the conserved proline residue

In terms of TLR signaling, it should be noted that TLR3 has a unique feature in its intracytoplasmic domain. It does not carry the proline residue that all other TLR family members retain (Fig. 2). Instead, the proline is replaced with alanine, and this replacement is conserved in both human and mouse TLR3. It will be interesting to characterize the signaling mechanism through TLR3 and to discover whether or how this replacement residue is involved in signaling.

TLR3 is unique in that it is

TLR family and Th2 immune response

It is possible that TLRs can influence DC differentiation. Evidence suggests that DCs can be divided into two subsets that are involved in stimulating type 1 and type 2 immune responses 5., 6.. It is unclear whether DC polarization is determined by the origin of the DCs or the type of DC stimuli, or both. TLR ligands identified to date mainly stimulate the ability of DCs to support Th1-cell differentiation. However, BM DCs, which can mature to ‘type 1’ DCs in response to LPS, can differentiate

Conclusions

At present, we have only discerned the tip of the iceberg where the signaling mechanism of the TLR family is concerned. Signaling through TLR4 is unique among TLRs in that LPS can stimulate both MyD88-dependent and -independent pathways. Both pathways can contribute to DC maturation and different TLRs activate similar but distinct signaling pathways. Thus, clarification of the TLR signaling mechanism is crucial to elucidate how DC maturation is regulated by bacteria and their products.

Acknowledgments

We thank our colleagues for helpful discussions and R.M. Torres for critically reading the manuscript. We apologize for not citing all the works in this field owing to space limitations. This work was supported in part by grants from the Ministry of Education, Science and Culture in Japan, Novartis Foundation (Japan) for the Promotion of Science, Kato Memorial Bioscience Foundation, Kowa Life Science Foundation, and CREST (Core Research for Evolutional Science and Technology) of the Japan

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