HVEM: a generator and a mediator of ADCC
Our work on the ΔgD-2 vaccine led us to two key observations regarding the generation and mediation of ADCC:
Generation: Cellular entry of HSV is primarily initiated by binding of gD to nectin-1, which is expressed on mouse and human epithelial, neuronal, and immune cells. However, gD also binds to the immunomodulatory molecule HVEM, a member of the TNFRSF, and blocks the interactions between HVEM and its natural ligands. We hypothesized that HVEM signaling is needed for the generation of ADCC Abs and that the absence of gD overcomes this immune evasion strategy. Our studies thus far have demonstrated that HVEM signaling facilitates the generation of ADCC-mediating Abs and by inhibiting interactions between HVEM and one or more of its ligands, gD impairs the generation of these protective responses.
Mediation: HSV can escape neutralizing Abs by spreading from infected to uninfected cells through cell junctions but cannot escape ADCC. We hypothesized that this immune evasion mechanism involves HVEM since gD binds to HVEM and inhibits interactions between HVEM and its natural ligands. Supporting our hypothesis, a reduction in HSV-specific IgG2c and ADCC responses to ΔgD-2 in Hvem-/- mice occurred, which translated into a loss in active and passive vaccine protection. Surprisingly, transfer of immune serum from ΔgD-2-vaccinated WT mice (replete with ADCC Abs) also failed to protect Hvem-/- mice. Similar results were obtained when we assessed ADCC using human parental or HVEM deficient reporter cells engineered to express human FcgRIIIa+.
Ongoing projects aim to tease out the mechanism behind both the generation and mediation arms of HVEM.
