Expression of the Receptor Tyrosine Kinase EphB2 on Dendritic Cells Is Modulated by Toll-Like Receptor Ligation but Is Not Required for T Cell Activation

Abstract

The Eph receptor tyrosine kinases interact with their ephrin ligands on adjacent cells to facilitate contact-dependent cell communication. Ephrin B ligands are expressed on T cells and have been suggested to act as co-stimulatory molecules during T cell activation. There are no detailed reports of the expression and modulation of EphB receptors on dendritic cells, the main antigen presenting cells that interact with T cells. Here we show that mouse splenic dendritic cells (DC) and bone-marrow derived DCs (BMDC) express EphB2, a member of the EphB family. EphB2 expression is modulated by ligation of TLR4 and TLR9 and also by interaction with ephrin B ligands. Co-localization of EphB2 with MHC-II is also consistent with a potential role in T cell activation. However, BMDCs derived from EphB2 deficient mice were able to present antigen in the context of MHC-II and produce T cell activating cytokines to the same extent as intact DCs. Collectively our data suggest that EphB2 may contribute to DC responses, but that EphB2 is not required for T cell activation. This result may have arisen because DCs express other members of the EphB receptor family, EphB3, EphB4 and EphB6, all of which can interact with ephrin B ligands, or because EphB2 may be playing a role in another aspect of DC biology such as migration.

The Roles of EphB2 in Cancer

“…In contrast, replacing them with glutamic acid, which like phosphotyrosine is negatively charged, will disrupt SH2 domain binding without impairing EphB2 kinase activity ( Zisch et al, 2000 ). Functionally, Ephb2 is related to monocyte adhesion to endothelial cells ( Vreeken et al, 2020 ), endothelial cell chemotaxis and branching remodeling ( Salvucci et al, 2006 ), T-cell and B-cell activation ( Nguyen et al, 2013 ; Yu et al, 2014 ; Mimche et al, 2015a ), autophagic cell death ( Kandouz et al, 2010 ; Tanabe et al, 2011 ), cell repulsive responses ( Lin et al, 2008 ; Poliakov et al, 2008 ; Schaupp et al, 2014 ; Gaitanos et al, 2016 ; Okumura et al, 2017 ; Evergren et al, 2018 ), platelet function ( Vaiyapuri et al, 2015 ; Berndt and Andrews, 2018 ; Berrou et al, 2018 ), angiogenesis ( Sato et al, 2019 ), and liver fibrosis ( Mimche et al, 2015b ; Butler and Schmidt, 2015 ; Mimche et al, 2018 ; Chen et al, 2020 ; Huang et al, 2021 ).…”

Emerging Roles for Eph Receptors and Ephrin Ligands in Immunity

“…There are very few reports on the contribution of Eph receptors and ephrin ligands to the activation of innate immune cells. However, there is evidence suggesting a role for Eph receptors, specifically EphB2, in modulating dendritic cell (DC) responsiveness to toll-like receptor (TLR) ligation by pathogen-associated molecular patterns (69). Although not currently understood, it is possible that TLR signaling pathways intersect with EphB forward signaling events leading to a modulation of NFκB activation which is central to many immune cell activation pathways.…”

“…Human DCs are also known to express members of the EphA (EphA2, EphA4, EphA7) and EphB (EphB1, EphB2, EphB3, EphB6) subfamilies (68, 69). Similar to monocytes, Eph receptors could potentially contribute to DC trafficking and adhesion by allowing for localization to sites of damage or infection in the body with some evidence suggesting that crosstalk between Eph receptors and integrins, particularly β1 integrin, may facilitate DC adhesion (68).…”

Immunobiology of Atherosclerosis: A Complex Net of Interactions

“…In macrophages, CD36 levels can be upregulated by curcumin-induced expression of nuclear factor (erythroid-derived 2)-like 2 (NFE2L2) [208], whereas in monocytes, CD36 is increased by LPS via upregulation of AP-1 transcription factors [209] and by palmitate [210]. CD36 can be inhibited by ceramides in monocytes [211] and by plant antioxidant in macrophages [212,213,214].…”