Model of HHV-8–associated MCD associated with diminished iNKT cells. (A) Controlled HHV-8 infection of B cells is associated with limited lytic activation of HHV-8 and effective immune surveillance by T cells and iNKT cells. Activated iNKT cells likely produce cytokines that further promote antiviral immunity in this setting. (B) HHV-8–associated MCD is associated with decreased iNKT cells. In addition, dysregulated lytic activation of HHV-8 leads to upregulation of the HHV-8–encoded E3 ubiquitin ligases K3 and K5, which downregulate CD1d and MHC-I and further promote immune evasion. Upregulation of human and viral IL-6 and other cytokines in this setting promotes proliferation of HHV-8–infected B cells. iTCR, invariant T-cell receptor; TCR, T-cell receptor; vIL-6, viral IL-6. Professional illustration by Patrick Lane, ScEYEnce Studios.