Untangling the Tlrs in TLR2 and TLR4 Signal-Transduction Pathways

HIGHLIGHTS

HIV Until recently, it was a mystery why activity of CAF by competing with some individuals infected with virus for binding to CCR5, which is HIV-1 do not become immunodefi- used as a co-receptor for virus entry. cient (long-term non-progressors, However, this can only inhibit R5 Identity of CAF revealed LTNPs). CD8+ T cells are known to viruses, and not X4 viruses, which be important, but why are they use CXCR4 as a co-receptor. Using more effective in some individuals protein-chip technology, Zhang et al. than others? A recent paper in have shown that the α-defensins carry Nature Immunology showed that the out much of the anti-HIV activity of increased expression of perforin by supernatants from stimulated CD8+ CD8+ T cells from LTNPs is impor- T cells that is not attributable to tant for their cytolytic activity (see β-chemokines. the Highlight ‘Quality control’ in The authors compared the protein our November issue). But, since the mass spectra of supernatants from first description of CD8 antiviral stimulated and unstimulated CD8+ factor (CAF) — which is secreted by T cells of LTNPs, normal progressors stimulated CD8+ T cells from certain and controls. Marked differences infected individuals — it has been between stimulated and unstimulated recognized that soluble factors can spectra were observed — specifically, inhibit virus replication also. Now, three peaks between 3.3 and 3.5 kD Zhang et al. report in Science the that were present in stimulated cul- identification of human α-defensins tures from LTNPs and some controls, 1, 2 and 3 as one of the main com- but not progressors. The three peaks ponents of CAF. correspond to the molecular masses Previous studies had indicated of human α-defensins 1, 2 and 3, and that β-chemokines (CCL3, CCL4 and this result was confirmed by protein CCL5) might account for the antiviral sequencing.

− − INNATE IMMUNITY not compromised in Tirap / mice. So, together, these papers show that TIRAP is dispensable for TLR3, TLR5, TLR7, TLR9 and IL-1R function, but has a specific role Untangling the TLRs in TLR2 and TLR4 signal-transduction pathways. Similar to MYD88, TIRAP has a crucial The Toll-like receptor (TLR) family function in this MYD88-independent role in the activation of nuclear factor-κB consists of ten germline-encoded microbe pathway. But, the Tirap-knockout mice and mitogen-activated protein kinases by sensors that are crucial for host defence. described by Yamamoto et al. and Horng TLR2 and TLR4. And Tirap−/− mice and The theory is that each receptor triggers et al. show that this is not the case. Myd88 −/− mice have similarly defective an innate immune response that is Horng and co-workers found that in responses to LPS, which indicates that appropriate for the class of pathogen that response to triggering of TLR2 or TLR4, TIRAP might be involved in a MYD88- the receptor recognizes. But, differences Tirap−/− B cells had impaired proliferative dependent pathway. To test this, Yamamoto between TLR signal-transduction pathways responses and Tirap−/− DCs produced and co-workers generated Myd88 −/−Tirap−/− that might result in such tailored responses markedly reduced levels of pro- mice. The LPS-induced upregulation of have been hard to find. Now, two studies inflammatory cytokines. But, responses to a expression of co-stimulatory molecules published in Nature show that the adaptor TLR9 ligand (CpG DNA) were normal in on DCs (a MYD88-independent event) molecule TIRAP (also known as MAL) has these cells, and injection of the TLR5 ligand occurred normally in these double- a restricted role in a shared TLR2 and TLR4 flagellin into Tirap−/− mice induced the knockout mice, so TIRAP is clearly not part signal-transduction pathway. expression of normal levels of cytokines. of the MYD88-independent pathway. TIRAP is structurally similar to the Yamamoto et al. showed that the Jennifer Bell adaptor protein MYD88, which links the production of pro-inflammatory cytokines References and links TLRs and interleukin-1 receptors (IL-1Rs) in response to LPS and various ligands for ORIGINAL RESEARCH PAPERS Yamamoto, M. et al. to downstream signalling pathways. MYD88 TLR2 is impaired markedly in Tirap−/− Essential role for TIRAP in activation of the signalling cascade shared by TLR2 and TLR4. Nature 420, 324–329 −/− is essential for the induction of cytokine macrophages. Furthermore, Tirap mice (2002) | Horng, T. et al. The adaptor molecule TIRAP secretion by all TLR ligands, but the were completely resistant to LPS-induced provides signalling specificity for Toll-like receptors. Nature lipopolysaccharide (LPS) receptor TLR4 can shock. But, the responses of Tirap−/− 420, 329–333 (2002) stimulate the upregulation of expression of macrophages to synthetic ligands for TLR7 FURTHER READING Medzhitov, R. Toll-like receptors and innate immunity. Nature Rev. Immunol. 1, 135–145 (2001) co-stimulatory receptors on dendritic cells and TLR3, and CpG DNA, were intact. WEB SITE −/− (DCs) in the absence of MYD88. Initial In contrast to Myd88 mice, both Ruslan Medzhitov’s lab: in vitro studies indicated that TIRAP might groups showed that IL-1 signalling is http://info.med.yale.edu/immuno/fac_medzhitov.html