Ig-like transcript 4 (ILT4) (also known as leukocyte Ig-like receptor 2, CD85d, and LILRB2) is a cell surface receptor expressed mainly on myelomonocytic cells, whereas ILT2 (also known as leukocyte Ig-like receptor 1, CD85j, and LILRB1) is expressed on a wider range of immune cells including subsets of natural killer and T cells. Both ILTs contain immunoreceptor tyrosine-based inhibitory receptor motifs in their cytoplasmic tails that inhibit cellular responses by recruiting phosphatases such as SHP-1 (Src homology 2 domain containing tyrosine phosphatase 1). Although these ILTs have been shown to recognize a broad range of classical and nonclassical human MHC class I molecules (MHCIs), their precise binding properties remain controversial. We have used surface plasmon resonance to analyze the interaction of soluble forms of ILT4 and ILT2 with several MHCIs. Although the range of affinities measured was quite broad (K d ‫؍‬ 2-45 M), some interesting differences were observed. ILT2 generally bound with a 2-to 3-fold higher affinity than ILT4 to the same MHCI. Furthermore, ILT2 and ILT4 bound to HLA-G with a 3-to 4-fold higher affinity than to classical MHCIs, suggesting that ILT͞HLA-G recognition may play a dominant role in the regulation of natural killer, T, and myelomonocytic cell activation. Finally, we show that ILT2 and ILT4 effectively compete with CD8 for MHCI binding, raising the possibility that ILT2 modulates CD8 ؉ T cell activation by blocking the CD8 binding as well as by recruiting inhibitory molecules through its immunoreceptor tyrosine-based inhibitory receptor motif.leukocyte Ig-like receptors ͉ major histocompatibility complex ͉ surface plasmon resonance ͉ natural killer cell ͉ coreceptor I g-like transcripts (ILTs) (also called leukocyte Ig-like receptors, CD85, or LILRB) are encoded by a family of immunoreceptor genes located at human chromosome 19q13.4. This locus is called the leukocyte receptor complex and includes, in addition to ILT genes, the genes encoding killer cell Ig-like receptors (KIRs), leukocyte-associated Ig-like receptors, NKp46, and the Fc␣ receptor (1). Although ILT2 is broadly expressed on monocytes, B cells, dendritic cells, and subsets of natural killer (NK) and T cells, ILT4 expression is largely confined to the myelomonocytic lineage (2-8). Both ILT2 and ILT4 have four tandem Ig-like extracellular domains and four and three immunoreceptor tyrosine-based inhibitory receptor motifs, respectively, in their cytoplasmic tails. Immunoreceptor tyrosine-based inhibitory receptor motifs recruit the protein tyrosine phosphatase SHP-1 (Src homology 2 domain containing phosphatase 1), which is thought to inhibit early signaling events triggered by stimulatory receptors. Indeed engagement of ILT2 on T cells has been shown to inhibit T cell antigen receptor (TCR) signaling and downstream events such as actin reorganization (9). Studies on CD8 ϩ cells suggest that ILT2 is expressed early on in contrast to KIRs, which are expressed primarily on the subset of stimulated CD8 ϩ cells tha...

Pore-forming toxins (PFT) are water-soluble proteins that possess the remarkable ability to self-assemble on the membrane of target cells, where they form pores causing cell damage. Here, we elucidate the mechanism of action of the haemolytic protein fragaceatoxin C (FraC), a α-barrel PFT, by determining the crystal structures of FraC at four different stages of the lytic mechanism, namely the water-soluble state, the monomeric lipid-bound form, an assembly intermediate and the fully assembled transmembrane pore. The structure of the transmembrane pore exhibits a unique architecture composed of both protein and lipids, with some of the lipids lining the pore wall, acting as assembly cofactors. The pore also exhibits lateral fenestrations that expose the hydrophobic core of the membrane to the aqueous environment. The incorporation of lipids from the target membrane within the structure of the pore provides a membrane-specific trigger for the activation of a haemolytic toxin.

No abstract