Fig. 2

BTLA interacts with HVEM in a cis and trans manner. Left panel: cis interactions. BTLA and HVEM are expressed on the same cell. The BTLA-HVEM cis interaction prevents BTLA or HVEM from interacting with other co-signaling molecules in a trans manner and inhibits HVEM-dependent NF-κB activation in the T-cell promoting tolerance. Right panel: trans interactions. BTLA and HVEM are expressed on different cells. The BTLA-HVEM trans interaction provides bidirectional signaling in T-cells. BTLA engagement leads to the recruitment of SHP-1 and SHP-2, thereby downregulating the TCR signaling and providing inhibitory signals. Conversely, binding of the GRb-2 protein leads to the activation of the PI3K/Akt signaling promoting T-cell survival