A coreceptor interaction between the CD28 and TNF receptor family members B and T lymphocyte attenuator and herpesvirus entry mediator

Abstract

The primary cosignaling receptors belong to either the Ig CD28-like or TNF receptor (TNFR) superfamilies (1-5). Currently, the CD28 family consists of five lymphoid-specific coreceptors [CD28, inducible T cell costimulator (ICOS), cytotoxic T lymphocyte antigen 4 (CTLA-4), programmed death-1 (PD-1), and B and T lymphocyte attenuator (BTLA)] (1-3). CD28 and ICOS are single Ig-variable (IgV) domain glycoproteins that promote T cell activation, whereas the structurally related CTLA-4, PD-1, and BTLA receptors function to attenuate T cell activation. To date, all of the ligands that have been described for the CD28-like family members belong to the B7 superfamily (1-3, 6-9). Six B7 family members have been described, all of which have conserved extracellular IgV and Ig-constant domains (3). In the TNFR-TNF superfamily, five receptor-ligand interactions have been described that act as positive regulators. These include OX40-OX40L, 4-1BB-4-1BBL, CD27-CD70, CD30-CD30L, and herpesvirus entry mediator (HVEM)-homologous to lymphotoxin, which shows inducible expression and competes with herpes simplex virus (HSV) glycoprotein D (gD) for HVEM, a receptor expressed by T lymphocytes (HVEM-LIGHT) (4).The most recently identified CD28 family member is the inhibitory coreceptor, BTLA (10-12). BTLA is expressed on developing B and T cells, all mature lymphocytes, splenic macrophages, and mature marrow-derived dendritic cells (10,11). BTLA contains a single IgV domain and two intracellular immunoreceptor tyrosine-based inhibitory motifs that are phosphorylated after BTLA coligation to antigen receptors, resulting in recruitment of protein tyrosine phosphatases SHP-1 and SHP-2 (13). Because of this, and that coligation of BTLA to the TCR inhibits T cell activation, BTLA is implicated as a negative regulator of T cell activation (10, 11). This finding is further supported by the observation that BTLA-deficient T cells show increased proliferation and that BTLA Ϫ͞Ϫ mice have increased Ab response and show increased incidence and severity to an autoimmune disorder (9, 10).Initially, BTLA was proposed to interact with a B7 family member called B7x (10, 14). This conclusion, however, was based on an indirect binding study testing the interaction of B7x-Ig fusion to spleen and lymph node cells from either WT or BTLA-deficient mice. Furthermore, we have been unable to detect any specific binding of BTLA-Fc to B7x-transfected cells (data not shown). Spurred by the inability to confirm the BTLA-B7x interaction, we screened a secreted protein library (15) by using surface plasmon resonance (SPR) and identified HVEM as a coreceptor for human BTLA.Here we show that BTLA and HVEM interact with high affinity and can form a trimeric complex with TNF ligands LIGHT or lymphotoxin ␣ (LT␣). Our binding studies suggest that BTLA interacts with the outer surface of the HVEM͞TNF complex, suggesting structural models for how HVEM might engage BTLA on the cell surface. Finally, we demonstrate that binding of HVEM to BTLA results in the inhibition of T cel...

4-1BBL Induces TNF Receptor-Associated Factor 1-Dependent Bim Modulation in Human T Cells and Is a Critical Component in the Costimulation-Dependent Rescue of Functionally Impaired HIV-Specific CD8 T Cells

“…Our studies failed to show any efficacy of LIGHT in human T cell activation, even though it was highly expressed on recombinant AdV modified-monocytes and capable of binding anti-LIGHT as well as its known receptors. Recent evidence shows that in addition to acting as a receptor for LIGHT, HVEM can function as a ligand for the immunoreceptor tyrosine inhibitory motif-containing receptor, B and T lymphocyte attenuator (55,56). Thus, it is possible that HVEM-B and T lymphocyte attenuator interaction predominates during T cell activation resulting in minimal impact of HVEM signaling in T cells.…”

The TNF receptor and Ig superfamily members form an integrated signaling circuit controlling dendritic cell homeostasis

“…Following HVEM engagement, BTLA attenuates antigen-mediated signals through an ITIM/ ITSM-dependent recruitment of Src homology tyrosine phosphatase-1 and -2 [27]. Biochemical analyses demonstrated that LIGHT and BTLA engage HVEM at distinct sites, suggesting that HVEM constitutes a molecular switch between positive and inhibitory signaling [28][29][30]. As LIGHT-deficient mice do not possess any apparent defect in DC subsets, we investigated whether the HVEM-BTLA interaction was involved in the regulation DC homeostasis.…”

B and T Lymphocyte Attenuator Regulates B Cell Receptor Signaling by Targeting Syk and BLNK

“…A stable BJAB cell line constitutively expressing human BTLA (BTLA-BJAB) was generated as described previously (4). In short, BJAB cells were infected with a murine stem cell virus-human BTLA construct (BD Biosciences) and BTLA expression was confirmed by flow cytometry (supplemental Fig.…”

“…Proteins were expressed in Chinese hamster ovary cells as detailed previously (4). Briefly, C-terminal Fc-fusion proteins were purified by affinity chromatography using MabSure select Sepharose (Amersham Pharmacia), eluted with acetate (pH 3), and neutralized with a 1/10 dilution of 1 M Tris (pH 8.0).…”

“…However, unlike PD-1 and CTLA-4, which bind members of the B7 Ig superfamily receptors, the established ligand for BTLA is the TNFR family member herpesvirus entry mediator (HVEM) (TNFRSF14) (3)(4)(5). HVEM binding leads to tyrosine phosphorylation of the cytoplasmic tail of BTLA, which contains a proposed Grb2/Grb2-related adaptor protein (Grap) docking site and two ITIMs (5)(6)(7)(8)(9)(10)(11).…”