Fig 9. Schema of HBZ mediated inhibition of inhibitory signaling from co-inhibitory receptors.

After T-cell activation through TCR, PD-1 forms microcluster with TCR complex. Complex containing SHP-2, Grb2 and THEMIS recruits to ITSM or ITIM motif of co-inhibitory receptors, PD-1 and TIGIT. SHP-1 dephosphorylates critical molecules for T-cell activation including ZAP-70 and CD3ζ. HBZ interacts with THEMIS, which changes subcellular localization of HBZ. HBZ interferes complex formation of THEMIS, Grb2 and SHP-2, which results in inhibition of suppressive signal from co-inhibitory receptors, and enhanced activation of T cells.