Chapter 16 : The Function of Leukocyte Immunoglobulin-Like Receptors in Self-Tolerance, Viral Recognition, and Regulation of Adaptive Responses

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The Function of Leukocyte Immunoglobulin-Like Receptors in Self-Tolerance, Viral Recognition, and Regulation of Adaptive Responses, Page 1 of 2

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To achieve self-tolerance, many inhibitory receptors recognize major histocompatibility complex class I (MHC-I) molecules, which are normally expressed on healthy cells. In humans, inhibitory MHC-I receptors include the killer cell immunoglobulin (Ig)-like receptors (KIRs), the leukocyte Ig-like receptors (LILRs), and the CD94/NKG2A heterodimer. This chapter focuses on LILRs and, in particular, on their function during cytomegalovirus (CMV) infection and their ability to regulate adaptive responses during bacterial infection and following organ transplantation. The members of the LILR family--also known as immunoglobulin-like transcript (ILT), leukocyte Ig-like receptor (LIR), monocyte and macrophage Ig-like receptor (MIR), or CD85--include at least 11 distinct molecules, which have either two or four homologous extracellular Ig-like domains of the C2 type. Inhibitory LILRs (LILRB1, LILRB2, LILRB3, LILRB4, and LILRB5) contain long cytoplasmic domains with two to four immunoreceptor tyrosine-based inhibitory motifs (ITIMs). Another group of LILRs (LILRA1, LILRA2, ILT7, ILT8, and ILT11) have short cytoplasmic domains that lack ITIMs or recognizable docking motifs for signaling mediators. If LILRs have evolved under the selective pressure of UL18, one would also expect that UL18 mutates to neutralize this strategy of the host immune system. A recent study suggests that the ability of inhibitory LILRs to regulate the function of antigen-presenting cells (APCs) may be an important mechanism utilized by suppressor T (Ts) cells to induce immunological tolerance.

Citation: Colonna M, Barchet W. 2004. The Function of Leukocyte Immunoglobulin-Like Receptors in Self-Tolerance, Viral Recognition, and Regulation of Adaptive Responses, p 301-312. In Kaufmann S, Medzhitov R, Gordon S (ed), The Innate Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555817671.ch16

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Major Histocompatibility Complex Class I
Immune Systems
Innate Immune System
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Image of FIGURE 1

Organization of the human LILR loci on human chromosome 19q13.4. LILR genes are organized in a centromeric and a telomeric gene cluster encoding inhibitory (LILRB3, LILRB5, LILRB2, LILRB1, and LILRB4), activating (ILT8, ILT11, ILT7, LILRA2, LILRA1), and soluble (LILRA3) isoforms.Two further LILR genes are pseudogenes (ILT9, ILT10, ψ). Schematic models of the encoded molecules are also shown. The five inhibitory LILRs comprise two to four extracellular Ig-like domains and signal through two to four ITIMs in the cytoplasmic domain. LILRB1 and LILRB2 recognize all MHC-I molecules but ligands for other inhibitory LILRs remain unknown. LILRA1 is shown as an example for activating LILRs that lack a cytoplasmic signaling domain but associate with the FcRγ adaptor via charged residues in the transmembrane region. FcRγ signals through an ITAM. LILRA3 is lacking cytoplasmic as well as transmembrane domains and is probably secreted as a soluble molecule. LILRs are also known as ILTs, LILRs, MIRs, or CD85. See the official HUGO nomenclature at http://www.gene.ucl.ac.uk/ nomenclature.

Citation: Colonna M, Barchet W. 2004. The Function of Leukocyte Immunoglobulin-Like Receptors in Self-Tolerance, Viral Recognition, and Regulation of Adaptive Responses, p 301-312. In Kaufmann S, Medzhitov R, Gordon S (ed), The Innate Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555817671.ch16
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Image of FIGURE 2

Evolving action and counteraction on the host pathogen interface. (I) In the absence of infection, inhibitory MHC-I receptors such as LILRB1 mediate self-tolerance. (II) Viral pathogens such as HCMV are capable of evading recognition by cytotoxic T cells by retaining antigen-presenting MHC-I molecules. Furthermore, they may exploit inhibitory tolerance by expressing a decoy ligand (UL18 for inhibitory LILRB1). (III) Coevolution with a species-specific pathogen may have provided the selective pressure to convert a duplicated receptor gene into a pathogen-specific activating isoform. (IV) Mutations that were identified in the contact residues of the viral decoy indicate a viral strategy to evade specific detection of infected cells by innate effectors. Endogenous molecules in the target cells are shown in black and viral proteins are depicted in gray.

Citation: Colonna M, Barchet W. 2004. The Function of Leukocyte Immunoglobulin-Like Receptors in Self-Tolerance, Viral Recognition, and Regulation of Adaptive Responses, p 301-312. In Kaufmann S, Medzhitov R, Gordon S (ed), The Innate Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555817671.ch16
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Differential expression of LILR on APCs regulates CD4 T-cell responses and a pattern emerges.TLR signaling in maturing APCs activates NF-κB, leading to the production of IL-12 and to a lesser degree IL-10. APCs activated in this fashion promote a Th1 response. Modlin and colleagues ( ) have shown that coengagement of activating LILRA2 can shift the balance toward enhanced production of IL-10 and a significant reduction in IL-12. CD4 T cells polarized by IL-10-producing APCs may deviate toward a Th2 phenotype. Strong Th2 bias has also been observed in mice deficient for the inhibitory LILR homolog PIR-B, presumably due to the dominance of activating PIRs (PIR-As). Chang and colleagues (2002) report that the presence of CD8 CD28 Ts cells induces the expression of inhibitory LILRB2 and LILRB4 on maturing APCs. Inhibitory LILR signals downmodulate NF-κB activity,APCs become tolerogenic, and CD4 T cells cocultured with tolerogenic APCs become unresponsive to further antigenic stimuli.

Citation: Colonna M, Barchet W. 2004. The Function of Leukocyte Immunoglobulin-Like Receptors in Self-Tolerance, Viral Recognition, and Regulation of Adaptive Responses, p 301-312. In Kaufmann S, Medzhitov R, Gordon S (ed), The Innate Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555817671.ch16
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