Inhibition of Inflammatory Responses by Leukocyte Ig‐Like Receptors
Introduction
The ability of cell surface receptors to counterregulate innate and adaptive components of inflammatory processes is a relatively new concept in the field of inflammation. In recent years, our view of inflammation has expanded from one in which the presence and amounts of proinflammatory stimuli dictated outcomes, to one in which the ability of cells to downregulate their responses to those activation signals via cell surface receptors is also a key component. This conceptual evolution has tremendous implications for understanding regulation of the balance between beneficial inflammation that protects against microbial assault and detrimental inflammation that damages host tissue. In addition, that understanding is expected to provide new therapeutic approaches to boosting deficient responses and tempering overly exuberant responses, each of which can be life threatening in certain contexts.
Over the past 10 years, a large number of inhibitory receptors expressed on cells of the immune system have been identified. An element common to most of these receptors is the presence of the immunoreceptor tyrosine–based inhibitory motif (ITIM) in their cytoplasmic regions. The extracellular domains of these receptors typically belong to either the Immunoglobulin (Ig) or C‐lectin superfamilies, but the mechanistic bases for how the receptors inhibit cell activation and inflammation emanate from their ITIMs.
A central family of ITIM receptors pertaining to counterregulation of inflammation consists of the inhibitory members of the leukocyte Ig‐like receptors (LILRs), termed LILRBs. Most cells of the innate and adaptive immune systems express at least one LILRB. The human LILRBs are encoded within the leukocyte receptor complex (LRC) located on chromosome 19q13.4. The LRC also includes genes encoding the killer cell Ig‐like receptors (KIRs) that are expressed primarily on natural killer (NK) cells and certain T cell populations, and which include ITIM‐bearing receptors that principally downregulate cytotoxicity responses to certain virally‐infected and transformed cells. However, as described later, the LILRBs are more broadly expressed on cell populations, are activated by a more diverse set of ligands, and as shown in animal studies, are clearly key negative regulators of inflammation in vivo. Hence, the focus of this chapter is on the biochemistry and immunobiology of the LILRBs.
Section snippets
LILRB1
cDNA encoding LILRB1, which is also termed leukocyte Ig‐like Receptor 1 and Ig‐like transcript 2 (see Table 1 for synonyms), was initially cloned from NK and B cell lines using oligonucleotides encoding consensus sequences of C2‐type Ig‐like domains (Samaridis and Colonna, 1997). LILRB1 was subsequently identified as a ligand for UL18, an MHC class I homologue encoded by human cytomegalovirus (Cosman et al., 1997). Shortly thereafter, it was also defined by a mAb that restored the lytic
LILRB2
LILRB2 was initially defined by two groups of investigators using similar methods. In one approach, LILRB2 was cloned from a human monocyte cDNA library screened with cDNA probes encoding members of the LILR family, including LILRB1 (Borges et al., 1997). In the other approach, cDNA encoding LILRB2 was amplified by reverse transcriptase PCR from myelomonocytic cells using primers for LILRB1 (Colonna et al., 1997). The clonings revealed that LILRB2, like LILRB1, has four Ig‐like domains (Fig. 1
LILRB3
A cDNA encoding LILRB3 was initially defined by reverse transcriptase PCR from myelomonocytic cells using primers for LILRB1 (Colonna et al., 1997). In contrast with LILRB1 and LILRB2, LILRB3 does not bind MHC class I (Allan 1999, Colonna 1998), and structural predictions do not favor MHC class I serving as a ligand for LILRB3 (Willcox et al., 2003). Hence, the immunobiology of LILRB3 may be more distinct from the roles of LILRB1 and LILRB2 than the latter two receptors are from each other.
Mouse LILRB4
Mouse LILRB4 was previously termed gp49B1 but was recently renamed LILRB4 by the Mouse Genome Informatics Group at The Jackson Laboratory. The molecule was initially defined in 1983 by a mAb that recognizes an epitope on macrophages and mast cells (Katz 1983, LeBlanc 1984). The molecule was subsequently defined in mast cells as a 49‐kDa glycoprotein (Katz et al., 1989), which was immunoaffinity purified to determine its amino‐terminal sequence and clone its cDNA (Arm 1991, Castells 1994). The
LILRB5
LILRB5 was initially defined by cDNA cloning from a human DC library using LILR family probes (Borges et al., 1997). NK cells express mRNA encoding LILRB5, but little is known about the expression of LILRB5 at the protein level. LIRB5 is unique among the human LILRBs in having only the two ITIMs analogous to those in LILRB1 that bind SHP‐1, and in that regard, the cytoplasmic domain of LILRB5 resembles that of mLILRB4. However, LILRB5 has four Ig‐like domains like LILRB1, LILRB2, and LILRB3.
PIR‐B
Although mouse PIR‐B has not been given an LILRB designation, it has a number of striking similarities with the human LILRBs, which make it likely that it is a reasonable homologue, if not orthologue, of one or more human LILRB. PIR‐B was originally discovered during attempts to clone the mouse orthologue of the human myeloid IgA receptor (a member of the human LRC on chromosome 19) by cross‐hybridization screening of mouse genomic DNA with a cDNA probe encoding the human receptor (Hayami 1997,
Conclusions
The accumulated in vitro and in vivo data leave little doubt that the constitutively expressed LILRBs play significant roles in preventing pathologic inflammation that could otherwise ensue from unchecked activation of cells of the innate and adaptive immune systems. Cells must overcome an appreciable level of inhibitory signals to initiate and sustain inflammation in vivo because of the presence of multiple LILRBs on relevant cell populations, the constitutive or readily inducible endogenous
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2012, Developmental and Comparative ImmunologyCitation Excerpt :Many of these stimulatory receptors are germline-encoded and belong to either the immunoglobulin superfamily (IgSF) (Barclay, 2003) or the C-type lectin superfamily (Weis et al., 1998). Examples of immunoregulatory proteins with stimulatory functions include Fc receptors (FcRs; Falk and Ravetch, 2006; Nimmerjahn and Ravetch, 2007, 2011; Takai, 2005), killer cell Ig-like receptors (KIRs; Parham, 2004; Stanietsky and Mandelboim, 2010; Vilches and Parham, 2002), leukocyte Ig-like receptors (LILRs; Brown et al., 2004; Katz, 2006; Thomas et al., 2010), triggering receptors expressed on myeloid cells (Ford and McVicar, 2009), natural cytotoxicity receptors (e.g. NKp30, NKp44, and NKp46; Biassoni et al., 2001; Yokoyama and Plougastel, 2003), CD94/NKG2 (Gunturi et al., 2004; López-Botet et al., 1997), NK receptor-P1 (NKRP1; Carlyle et al., 2004), and Ly49 receptors (Anderson et al., 2001). In addition to these stimulatory forms, inhibitory receptor-types also play an indispensible role in the regulation of cellular immune responses (Long 2008, Long et al. 1997 and Steevels and Meyaard 2011).