The Cytomegalovirus mimic of Herpesvirus entry mediator avoids CD160 and inhibits IL-2 signaling through B and T lymphocyte attenuator restricting Natural Killer cell function (178.20)

Abstract

Abstract Natural killer (NK) cells express multiple activating receptors that, upon engagement, result in the rapid release of cytolytic and antiviral effectors required for host defense, notably against herpesviruses. The host is protected from the powerful inflammatory mediators produced by NK cells through the action of inhibitory receptors that typically associate with major histocompatibility class I proteins. To develop into fully functional effector cells and to maintain homeostasis, NK cells depend upon common γ chain signaling. Here, we show that the ORF UL144 mimic of herpesvirus entry mediator (HVEM, TNFRSF14) from the β-herpesvirus cytomegalovirus (CMV), binds exclusively to B and T lymphocyte attenuator (BTLA) but not to CD160, resulting in inhibition of IL-2-mediated activation of NK cells. HVEM and the two Ig-superfamily member receptors that bind HVEM, CD160 and BTLA, are all expressed on NK cells. Mechanistically, UL144 association with BTLA results in dephosphorylation of JAK1 and STAT5, resulting in decreased strength and duration of IL-2 receptor signaling. Subsequently, inhibition of IL-2 receptor signaling by UL144-BTLA suppresses NK cell activation and the ability of NK cells to express antiviral cytokines. Taken together, our results show a novel mechanism by which CMV can control the activation of NK cell antiviral effector functions via UL144-BTLA interactions that result in inhibition of IL-2 receptor signaling.