BTLA-HVEM interaction delivers bidirectional signals and modulates the severity of GVHD

Abstract B and T lymphocyte attenuator (BTLA), upon interaction with herpesvirus entry mediator (HVEM), delivers an inhibitory co-signal which regulates immune response in various diseases. In graft-versus-host disease (GVHD), unexpectedly, BTLA mediates positive effects on donor T cell survival, but immunological mechanisms of this function have yet to be fully explored. Our recent studies addressed a role of BTLA in GVHD by employing the newly established agonistic anti-BTLA mAb that stimulates BTLA signal without antagonizing BTLA-HVEM interaction. We revealed that BTLA signal inhibited donor anti-host T cell responses and ameliorated GVHD with a successful engraftment of donor hematopoietic cells. These effects were dependent on BTLA signal into donor T cells but neither donor non-T cells nor recipient cells. On the other hand, expression of BTLA mutant lacking an intracellular signaling domain restored impaired survival of BTLA-deficient T cells, suggesting that BTLA also serves as a ligand and delivers HVEM prosurvival co-signal in donor T cells. Thus, BTLA-HVEM interaction delivers positive and negative bidirectional co-signals to donor T cells via HVEM and BTLA, respectively, and modulates the severity of GVHD. Additional data obtained by recent studies will be also presented.