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Review
. 2019 Jul 4:10:1473.
doi: 10.3389/fimmu.2019.01473. eCollection 2019.

Emerging Roles for Eph Receptors and Ephrin Ligands in Immunity

Thayer K Darling  1   2 , Tracey J Lamb  2
Affiliations
Review

Emerging Roles for Eph Receptors and Ephrin Ligands in Immunity

Thayer K Darling et al. Front Immunol. .

Abstract

Eph receptors are the largest family of receptor tyrosine kinases and mediate a myriad of essential processes in humans from embryonic development to adult tissue homeostasis through interactions with membrane-bound ephrin ligands. The ubiquitous expression of Eph receptors and ephrin ligands among the cellular players of the immune system underscores the importance of these molecules in orchestrating an optimal immune response. This review provides an overview of the various roles of Eph receptors and ephrin ligands in immune cell development, activation, and migration. We also discuss the role of Eph receptors in disease pathogenesis as well as the implications of Eph receptors as future immunotherapy targets. Given the diverse and critical roles of Eph receptors and ephrin ligands throughout the immune system during both resting and activated states, this review aims to highlight the critical yet underappreciated roles of this family of signaling molecules in the immune system.

Keywords: Eph; activation; adhesion; cell trafficking; disease; ephrin; inflammation; migration.

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Figures

Figure 1
Figure 1
Basic Eph receptor structure and signaling pathways. The structure of Eph receptors and their ligands is shown in (A). Eph receptors are consisting of an extracellular structure consisting of an ephrin binding domain connected to two fibronectin type-III repeats by a cysteine-rich EGF-like motif. The juxtamembrane region connects the extracellular portion of the receptor to the intracellular kinase domain that is linked to a sterile alpha motif (SAM) domain and PDZ-binding motif. Two tyrosine residues on the juxtamembrane region mediate autophosphorylation. Eph receptors bind to ephrin ligands via an extracellular Eph binding domain. Ephrin-A ligands are GPI-anchored to the plasma membrane and signal through co-receptors that have not yet been fully defined. Ephrin-B ligands are transmembrane and are linked to an intracellular PDZ-binding motif via a linker containing five tyrosine resides for autophosphorylation. (B) Dimerization of Eph receptors is regulated by various processes including SAM domain interactions, ligand clustering, and interactions between cysteine-rich regions and ephrin binding domains on neighboring receptors. Receptor dimerization mediates the formation of heterocomplexes that are required for signaling and are assembled via the Eph receptor PDZ-binding motif. Formation of the heterocomplex mediates bi-directional signaling in which numerous signaling pathways known to play a role in immune cell function can be activated through both ephrin “reverse” and Eph “forward” signaling. These signaling events include activation of Rho GTPases, MAP kinases, PI3 kinase, Src family kinases, Jak-STAT molecules, and RGS3 that has been shown to suppress G-protein coupled receptors including chemokine receptors. P, representative of tyrosine phosphorylation sites; GPCRs, G-protein coupled receptors; RGS3, regulator of G-protein signaling 3; Grb4, cytoplasmic protein NCK2; PI3K, phosphatidylinositol 3-kinase; AKT, protein kinase B; Cdc42, cell division control protein 42 homolog; Ras-GAP, Ras-GTPase-activating protein; Erk, extracellular signal-regulated kinases; Jak, Janus kinase; STAT, signal transducer and activator of transcription; IL, interleukin.
Figure 2
Figure 2
Examples of the contribution of Eph receptors and ephrin ligands to both localized and systemic immune cell trafficking. Several systemic (A,B) and localized (C,D) roles of Eph-ephrin interactions in immunity are shown. (A) Both leukocytes, such as monocytes and T cells, and vascular endothelial cells, shown here in the brain as an example, express various Eph receptors and ephrin ligands. Eph-ephrin interactions can aid in processes such as leukocyte chemotaxis, adhesion, and transmigration of the vascular endothelium. These binding events can subsequently induce increased expression of adhesion molecules and integrins leading to enhanced cell-cell contact. (B) EphA receptors, primarily EphA2, on high endothelial venules (HEVs) of lymph nodes can interact with ephrin-A ligand-expressing T cells to facilitate trafficking between the blood and lymph. Additionally, ephrin-A1 on HEVs can bind EphA receptors on circulating peripheral T cells leading to changes in actin polymerization in the T cell and initiating subsequent chemotaxis. (C) Thymic organization as well as thymocyte development are heavily dependent on Eph-ephrin interactions. The Eph B family members are particularly important in these processes, with both single- and double-positive thymocytes as well as thymic epithelial cells (TECs) expressing several EphB receptors and ephrin-B ligands to facilitate cellular organization of the thymus and thymocyte selection. (D) EphB-ephrin-B interactions are critical for optimal germinal center interactions between B cells and T follicular helper (TFH) cells. Ephrin-B1 marks a subpopulation of germinal center memory B cells and binding to EphB4 and EphB6 on TFH cells induces IL-21 production from the TFH cells and repulsion, respectively, both required for optimal germinal center B cell cycling.
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