A recent study provided indirect evidence that B7X could be a ligand for B- and T-lymphocyte attenuator (BTLA). However, new data published in Nature Immunology shows that BTLA does not interact with B7X and that herpesvirus-entry mediator (HVEM) binds BTLA, initiating signalling pathways that impair antigen-induced T-cell proliferation.

The observation that binding of a B7X–Fc fusion protein to BTLA-deficient lymphocytes was reduced compared with binding to BTLA-sufficient lymphocytes led to the idea that B7X might be a BTLA ligand. So, Sedy et al. set out to find further evidence of this interaction. However, BTLA tetramers did not bind a B7X-expressing fibroblast cell line, and a B7X–Fc fusion protein did not bind BTLA-expressing cell lines. So, further studies in search of a BTLA-binding partner were carried out.

The physiological ligand for BTLA was first characterized using a BTLA–Fc fusion protein and was found to be expressed by resting T cells. A subsequent cDNA-library screen for cDNA encoding a BTLA-tetramer-binding protein indicated that the tumour-necrosis-factor receptor (TNFR)-family member HVEM was the BTLA-binding protein. Further studies then showed that BTLA bound the most membrane-distal cysteine-rich domain of HVEM. Binding of HVEM to BTLA induced tyrosine phosphorylation of BTLA and its association with SHP2 (SRC-homology-2-domain-containing protein tyrosine phosphatase 2). Furthermore, HVEM expression by antigen-presenting cells impaired peptide-mediated T-cell stimulation (in the presence or absence of co-stimulation) in a manner that was dependent on T-cell expression of BTLA.

This study identifies HVEM as the ligand of BTLA, and this interaction between a TNFR and an immunoglobulin-superfamily member is structurally unique. Although further studies are needed to define the in vivo significance of this interaction, the authors suggest that it is an important pathway for regulating lymphocyte activation and/or homeostasis.