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Review
, 8 (5), 327-36

Immunobiology of the TAM Receptors

Affiliations
Review

Immunobiology of the TAM Receptors

Greg Lemke et al. Nat Rev Immunol.

Abstract

Recent studies have revealed that the TAM receptor protein tyrosine kinases--TYRO3, AXL and MER--have pivotal roles in innate immunity. They inhibit inflammation in dendritic cells and macrophages, promote the phagocytosis of apoptotic cells and membranous organelles, and stimulate the maturation of natural killer cells. Each of these phenomena may depend on a cooperative interaction between TAM receptor and cytokine receptor signalling systems. Although its importance was previously unrecognized, TAM signalling promises to have an increasingly prominent role in studies of innate immune regulation.

Figures

Figure 1
Figure 1. TAM receptors and their ligands
TYRO3 (also known as BRT, DTK, RSE, SKY and TIF), AXL (also known as ARK, TYRO7 and UFO) and MER (also known as EYK, NYM and TYRO12) are receptor protein tyrosine kinases (PTKs) that are expressed by dendritic cells, macrophages and immature natural killer (NK) cells of the immune system, Sertoli cells of the testis, retinal pigment epithelial (RPE) cells of the eye, and several other cell types. TAM receptor dimers bind to their two ligands, growth-arrest-specific 6 (GAS6) and protein S, through interaction between the two N-terminal immunoglobulin-like domains of the receptors and the two C-terminal laminin G (LG) regions, which together make up the SHBG (sex hormone binding globulin) domain, of the ligands. (The solved X-ray crystal structure of the GAS6 SHBG domain bound to the immunoglobulin domains of AXL reveals that both ligand and receptor crystallize as dimers.) Via their N-terminal Gla domains, GAS6 and protein S then bind to phosphatidylserine that is displayed on the extracellular surface of the plasma membranes of apoptotic cells or on the outer segments of photoreceptors. EGF, epidermal growth factor; FNIII, fibronectin type III.
Figure 2
Figure 2. An inflammation cycle regulated by TAM signalling
Quiescent macrophages and dendritic cells (DCs) are stimulated by pathogen encounter, which activates Toll-like receptor (TLR) signalling pathways (yellow). This results in an initial burst of pro-inflammatory cytokines, the levels of which are then greatly amplified in a feed-forward loop through cytokine receptor signalling pathways (green). Cytokine signalling also drives the upregulation of expression of the TAM receptor AXL, which engages TAM receptor signalling pathways (red). These result in the induction of expression of suppressor of cytokine signalling 1 (SOCS1) and SOCS3, which broadly inhibit both TLR and cytokine receptor cascades, thereby ending the inflammatory response. TAM receptor signalling requires coordinate interaction with both the type I interferon receptor (IFNAR) and the transcription factor STAT1 (signal transducer and activator of transcription 1), which is also used for both cytokine amplification and the upregulation of AXL. AP1, activator protein 1; GAS6, growth-arrest-specific 6; IKK, inhibitor of NF-κB kinase; IFNα, interferon-α; IRAK, interleukin-1-receptor-associated kinase; IRF, interferon-regulatory factor; JAK, Janus kinase; MAL, MyD88-adaptor-like protein; MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor-κB; TAB, TAK1-binding protein; TAK1, transforming-growth-factor-β-activated kinase 1; TBK1, TANK-binding kinase 1; TRAF, tumour-necrosis-factor-receptor-associated factor; TRAM, TRIF-related adaptor molecule; TRIF, Toll/interleukin-1-receptor-domain-containing adaptor protein inducing interferon-β.
Figure 3
Figure 3. TAM signalling and the ‘homeostatic phagocytosis’ of apoptotic cells and membranes
TAM receptor signalling is required for the clearance of apoptotic cells in fully differentiated adult tissues and organs that undergo constant challenge, renewal and remodelling. These include the testis, where Sertoli cells clear the large number of apoptotic cells that are generated during spermatogenesis (a); the retina, where retinal pigment epithelial (RPE) cells pinch off the distal ends of photoreceptor outer segments (b); and the lymphoid organs, where macrophages and dendritic cells remove apoptotic cells generated by infection (c). Each of these events is dramatically impaired in mice that lack TAM receptors. A significant fraction of TAM receptor signalling in macrophages, RPE cells and Sertoli cells appears to be autocrine and/or paracrine, in that each of these TAM+ cells also express the TAM receptor ligands growth-arrest-specific 6 (GAS6) and/or protein S.
Figure 4
Figure 4. TAM signalling and the maturation of NK cells
Natural killer (NK)-cell differentiation proceeds through five stages, which are delimited by the expression of markers such as CD122, NK1.1 and Ly49s (a). TAM receptor signalling is required for NK-cell maturation during stage III. In this instance, growth-arrest-specific 6 (GAS6) and protein S are produced by stromal cells of the bone-marrow niche, and activate the TAM receptors, TYRO3, AXL and MER, that are expressed by immature NK cells (b). In the absence of TAM receptor signalling, these immature NK cells do not acquire expression of the inhibitory and activating receptors (for example, Ly49) required for target-cell recognition and killing. TAM receptor signalling may require interaction with a cytokine receptor signalling system — in this case, the interleukin-15 receptor (IL-15R), as physical and physiological interactions between the α-subunit of the IL-15R and AXL have been demonstrated.

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