B and T lymphocyte attenuator (BTLA) is an Ig superfamily coinhitory 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, reduced effectiveness of T regulatory cells. BTLA takes 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 effectors and naïve T cells. BTLA may cooperate with CTLA-4 and PD-1 to control T cell tolerance and autoimmunity. It was reported that BTLA may regulate T cell function by binding to B7-H4. But further studies are needed to confirm. The existence of three distinct BTLA alleles was reported. The BTLA antibody reacts only with the C57BL/6 allele of BTLA but not the BALB/c allele of BTLA.