UC San Diego

B and T lymphocyte attenuator (BTLA) is a co-inhibitory receptor expressed on T cells and B cells that is structurally and functionally related to programmed death protein-1 (PD-1), a well-established cancer immunotherapy target. Binding of T cell specific BTLA with its ligand HVEM on antigen-presenting cells triggers tyrosine phosphorylation of the intracellular tail of BTLA, and ultimately leads to suppression of the T cell response. There is growing interest in targeting BTLA for cancer immunotherapy, yet very little is known about its biochemical mechanism and potential crosstalk with PD-1. Using a well-defined liposome reconstitution system with purified recombinant proteins, we quantitatively compared the biochemical specificities of BTLA and PD-1 and dissected the roles of each tyrosine residues within BTLA using purified BTLA proteins containing point mutants. These experiments reveal unexpected differences in BTLA and PD-1 specificities, which might underlie their functional disparities.