B and T lymphocyte attenuator (BTLA) is an Ig superfamily coinhibitory receptor with structural similarity to programmed cell death 1 (PD-1) and CTLA-4. BTLA is expressed on B cells, T cells, macrophages, dendritic cells, NKT cells, and NK cells. Engagement of BTLA by its ligand Herpes Virus Entry Mediator (HVEM) is critical for negatively regulating immune response. The absence of BTLA with HVEM inhibitory interactions leads to increased experimental autoimmune encephalomyelitis severity, enhanced rejection of partially mismatched allografts, an increased CD8+ memory T cell population, increased severity of colitis, and reduced effectiveness of T regulatory cells. BTLA plays an important role in the induction of peripheral tolerance of both CD4+ and CD8+ T cells in vivo. Tolerant T cells have significant up-regulated expression of BTLA compared with effector and naïve T cells. BTLA may cooperate with CTLA-4 and PD-1 to control T cell tolerance and autoimmunity. It has been reported that BTLA may regulate T cell function through binding to B7-H4.