Innate immune recognition by stimulatory immunoreceptors
Introduction
Stimulatory immunoreceptors occupy center stage in the recognition of foreign antigens or pathogens by the immune system. Archetypal examples of stimulatory immunoreceptors are the B cell receptor (BCR) and T cell receptor (TCR), which are encoded by rearranging genes and are the major structures employed by B and T cells to discriminate between self and nonself molecules. Stimulatory immunoreceptors are multisubunit structures composed of ligand-binding subunits (e.g. the TCR α and β chains and the BCR heavy and light chains) and associated transmembrane signaling adaptor protein(s). The cytoplasmic domains of adaptor proteins contain an immunoreceptor tyrosine-based activation motif (ITAM) with the consensus sequence YxxL/Ix6-8YxxL/I (with x representing any amino acid, the other residues are represented by amino acid one-letter code). The TCR associates with several adaptor proteins including the TCRζ chain (also called CD3ζ), and the BCR associates with the Igα and Igβ adaptor proteins. Crosslinking of stimulatory immunoreceptors leads to activation of the corresponding cells and initiates immune responses against pathogens and tumors.
The cells of the innate immune system do not express highly diversified receptors encoded by rearranging genes. Instead, they express various other stimulatory immunoreceptors that also associate with ITAM-containing signaling adaptor proteins, including CD3ζ, FcRγ and killer cell-activating receptor-associated protein (KARAP, also called DAP12). The biological roles of many of these receptors are not well understood, primarily because many of the ligands have not been identified and genetic loss-of-function studies have not yet been carried out in most cases.
This review focuses on three stimulatory receptor systems that fulfill very distinct functions in the innate immune response: NKG2D, Ly49H and the triggering receptors expressed by myeloid cells (TREMs). These three receptor systems illustrate distinct paradigms of how innate immune recognition via stimulatory receptors is achieved.
NKG2D is a stimulatory receptor expressed by lymphoid and myeloid cells that recognizes various cell surface ligands that are distantly related to class I MHC molecules and upregulated in infected, transformed or stressed cells [1]. Ly49H is expressed by a subset of NK cells and directly recognizes a viral gene product from mouse cytomegalovirus (MCMV), suggesting that this receptor may be involved in the immune response to viruses 2.••, 3.••, 4.••, 5.••, 6.••. The TREMs are a small family of stimulatory receptors exclusively expressed by myeloid cells. The ligands for these receptors are unknown. However, the blockade of TREM-1 in mice prevents various types of sepsis syndromes, suggesting that this receptor is involved in enhancing innate immune responses to several types of pathogens [7••]. All of these immunoreceptors use the KARAP/DAP12 molecule as a signaling adaptor protein (6.••, 7.••, see also Update).
Section snippets
Stimulatory receptors expressed by NK cells
The activation of NK cells is regulated by a balance of signals received from inhibitory and stimulatory receptors. NK cells are known to be activated by many tumor cells and virus-infected cells. How NK cells selectively recognize these cells is largely unknown. NK cells express various families of inhibitory receptors, all of which interact with class I MHC molecules. These receptors prevent NK cells from attacking normal self cells, while allowing them to attack cells that downregulate class
NKG2D receptor and its expression
NKG2D is expressed by various lymphoid and myeloid cells. In mice, NKG2D is expressed by all NK cells, by all epidermal γδ T cells, and by subsets of NKT cells and splenic γδ T cells (but not by intestinal epithelial γδ T cells) 11., 12.••. Additionally, NKG2D is expressed by essentially all CD8+ T cells after T cell receptor triggering and by macrophages after stimulation with LPS, IFN-γ or IFN-α/β 11., 12.••. In humans a slightly different expression pattern is observed; in addition to NK
Direct recognition of viral proteins by NK cells
Ly49H is another stimulatory receptor expressed by NK cells. Ly49H is a C-type lectin-like receptor that is a member of the Ly49 family of MHC class I-specific receptors [38]. In contrast to the majority of the Ly49 molecules, Ly49H does not contain an immunoreceptor tyrosine-based inhibition motif (ITIM) in its cytoplasmic domain. Instead, Ly49H associates with the signaling adaptor protein KARAP/DAP12, which contains an ITAM and couples the Ly49H receptor to the syk/ZAP70 signaling pathway
Stimulatory receptors expressed by myeloid cells
Several stimulatory receptors have been identified over the years that are expressed by myeloid cells and signal through ITAM-containing adaptor proteins, usually KARAP/DAP12 [42]. As discussed above, NKG2D is one receptor of this type 11., 12.••. The specificities and biological functions of most of the other receptors in this category are unknown. Recently, the TREM family of receptors has attracted considerable attention based on evidence that one family member (TREM-1) participates in the
The TREM family
Five Trem genes have been identified to date, four of which (Trem 1–4) encode potentially functional type I transmembrane glycoproteins [43]. The Trem genes are clustered on mouse chromosome 17/human chromosome 6. TREMs display a single extracellular Ig-like domain. For signaling, all known TREMs associate with the KARAP/DAP12 signaling adaptor protein 43., 44., 45., 46.. Interestingly, the TREMs are distantly related to a stimulatory receptor expressed by human NK cells, NKp44 47., 48.. NKp44
Perspectives
Stimulatory receptors on lymphoid and myeloid cells are multisubunit receptor complexes composed of extracellular ligand-binding subunits that associate with various ITAM-containing signaling molecules. Some of these receptors are primary immune recognition receptors (e.g. BCR, TCR, Ly49H), whereas others may act as amplifiers of a response (TREMs may fall into this category). NKG2D does both, functioning as a primary stimulatory receptor on NK cells and macrophages and as a co-stimulatory
Update
Recent studies have shed light on how the NKG2D receptor provides different signals in different cell types. Two NKG2D splice variants associate with different signaling adaptor proteins, resulting in qualitatively different signals [52••]. In CD8+ T cells, NKG2D associates solely with the signaling molecule DAP10, which provides a primarily co-stimulatory signal. In NK cells and macrophages, by contrast, NKG2D associates with both DAP10 and the ITAM-containing KARAP/DAP12 signaling molecule,
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
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of special interest
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of outstanding interest
Acknowledgements
AD is a Physician Postdoctoral Fellow of the Howard Hughes Medical Institute. Work from this laboratory is supported by grants from the National Institutes of Health to DHR.
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