EphrinB1 Is Essential in T-cell-T-cell Co-operation during T-cell Activation

Abstract

Eph kinases are the largest family of receptor tyrosine kinases, and their ligands are ephrins (EFNs), which are also cell surface molecules. We have very limited knowledge about the expression and function of these kinases and their ligands in the immune system. In this study we investigated the effect of EFNB1 on mouse T-cells. EFNB1 and the Eph kinases it interacts with (collectively called EFNB1 receptors (EFNB1R)) were expressed on T-cells, B cells, and monocytes/macrophages. Some T-cells were double positive for EFNB1 and EFBB1R. Solid phase EFNB1 in the presence of suboptimal TCR ligation augmented T-cell responses in terms interferon-␥ secretion, proliferation, and cytotoxic T lymphocyte activity but not interleukin-2 production. After T-cell receptor (TCR) ligation, EFNB1R congregated to TCR caps, and then both of them translocated to raft caps. This provides a morphological basis for EFNB1R to enhance TCR signaling. Further downstream of the signaling pathway, EFNB1R stimulation led to increased LAT (linker for activation of T-cells) phosphorylation and p44/42 and p38 MAPK activation. Similar to CD28 costimulation, EFNB1R costimulation was insensitive to cyclosporin A inhibition. On the other hand, unlike the former, EFNB1R costimulation failed to activate Akt, which is essential in triggering interleukin-2 production. Our study suggests that EFNB1 is pivotal in T-cell-T-cell costimulation and in reducing T-cell response threshold to antigen stimulation.

Reduced blood pressure after smooth muscle EFNB2 deletion and the potential association of EFNB2 mutation with human hypertension risk

“…Its reverse signaling depends on adaptor proteins associating with the tail. EFNB2 intracellular tails are characterized by two major features: the C-terminal PDZ domain-binding motif and five conserved tyrosine residues, which could be associated with PDZ domaincontaining proteins (eg, PDZ-RGS3, GRIP1/2, TIAM1 and DISHEV-ELED) 3,17,21,37,38 and SH2 domain-containing proteins (eg GRB4, STAT3 and CRK, 39 respectively). These two features are located in the last 31 aa, which are highly conserved.…”

“…3,4,[12][13][14][15][16][17][18][19][20][21][22] They are also vital in many biological processes; 5,6,23,24 however, until our recent publications, there were no studies investigating the roles of these molecules in blood pressure (BP) regulation.…”

Efnb1 and Efnb2 Proteins Regulate Thymocyte Development, Peripheral T Cell Differentiation, and Antiviral Immune Responses and Are Essential for Interleukin-6 (IL-6) Signaling

“…We have shown that Efnb1, Efnb2, and Efnb3 initiate signaling through their Eph receptors and can costimulate peripheral T cells in terms of enhancing cytokine production and proliferation in vitro (25)(26)(27). We further demonstrated that one of these Efnb receptors, Ephb6, although lacking kinase activity, can transmit signals into T cells (28) and that its null mutation leads to compromised T cells responses in vitro and in vivo (29).…”

“…Flow Cytometry-Single cell suspensions from the thymus, spleen, or lymph nodes were prepared and stained for flow cytometry as described in our previous publications (25)(26)(27)(28)(29) tetrameric complexes were synthesized in-house and used at 1:100 dilution as described previously (30). These MHC tetramers were used to detect LCMV-specific CD8 ϩ T cells.…”

Rab27b is associated with fusiform vesicles and may be involved in targeting uroplakins to urothelial apical membranes

“…The urothelium accomplishes this by forming a top layer of highly differentiated umbrella cells that elaborate a specialized apical asymmetric unit membrane. This unique membrane structure is composed mainly of four integral membrane proteins, the uroplakins Ia, Ib, II, and III (1)(2)(3)(4)(5)(6). These proteins begin to assemble in the endoplasmic reticulum where they form specific dimers (7)(8)(9), and they assemble further in a post-Golgi compartment represented by discoidal vesicles, where they form increasingly larger crystalline arrays composed of 16-nm hexagonal particles (1,(10)(11)(12)(13).…”