Disruption of Akt kinase activation is important for immunosuppression induced by measles virus

Abstract

Surface-contact-mediated signaling induced by the measles virus (MV) fusion and hemagglutinin glycoproteins is necessary and sufficient to induce T-cell unresponsiveness in vitro and in vivo. To define the intracellular pathways involved, we analyzed interleukin (IL)-2R signaling in primary human T cells and in Kit-225 cells. Unlike IL-2-dependent activation of JAK/STAT pathways, activation of Akt kinase was impaired after MV contact both in vitro and in vivo. MV interference with Akt activation was important for immunosuppression, as expression of a catalytically active Akt prevented negative signaling by the MV glycoproteins. Thus, we show here that MV exploits a novel strategy to interfere with T-cell activation during immunosuppression.

Expansion of human γ/δ T cells in vitro is differentially regulated by the measles virus glycoproteins

“…Results obtained can be summarized in that inhibition of lymphocyte proliferation by MV can result from direct infection (Naniche et al, 1999;Yanagi et al, 1992) or by indirect mechanisms such as yet undefined soluble mediators released from infected cells (Fujinami et al, 1998) or surface contactmediated signalling, which required interaction of the MV gp complex on few infected cells and an as yet unknown receptor on uninfected cells (Schlender et al, 1996). In the latter system, negative signalling by the MV effector F/H complex was shown to disrupt intracellular signalling pathways associated with the IL-2R heterotrimer (Avota et al, 2001), and this could explain why, in spite of normal expression levels of the IL-2R chains, mitogen-stimulated primary T cells cannot expand upon IL-2 addition after contact with the MV effector complex. The signal imposed on primary T cells did not induce cellular apoptosis but rather retarded S phase entry (Avota et al, 2001;Schnorr et al, 1997a).…”

“…In spite of their nonproliferating state, mitogen-stimulated T cells produced normal levels of cytokines, including IL-2, and upregulated early activation markers, also including the IL-2R a-subunit (CD25). The latter findings suggested defects in IL-2R signalling and indeed, the IL-2-dependent activation of the phosphatidylinositol-3-kinase (PI3K)/Akt kinase pathway was disrupted (Avota et al, 2001). Although this finding explained why MV gp-contacted T cells did not resume proliferation even upon the addition of exogenous IL-2, the molecular basis for the resistance of the unresponsive state to other exogenous stimuli, such as PMA/ionomycin and mitogens, is as yet unknown.…”

Measles virus hemagglutinin triggers intracellular signaling in CD150-expressing dendritic cells and inhibits immune response

“…Although CD150-induced activation of Akt phosphorylation was observed in T and B lymphocytes 20,22 , UV-inactivated vaccine strain of MV was shown to inhibit IL-2 dependent activation of Akt pathway in T cells 33 . These disparities may be linked to differences in the cell types and viral strains, distinct mode of cell activation and finally surface interaction of lymphocytes with the MV glycoprotein complex independently of CD150.…”

“…To be able to analyze DC-MV-H interaction in the absence of infectious context, we have generated CHO cell line stably expressing MV-H (CHO-H cells). This line allowed us to focus our study to the role of MV-H protein in the absence of other MV proteins, including fusion protein and nucleoprotein, both known to have biological activity [33][34][35] . Obtained CHO-H cell line stably expresses MV-H from the wt MV strain at the level comparable to MV-H expression on PBLs, infected with wt MV (Figure 1).…”

“…MV was shown to disrupt Akt kinase activation in T cells and this modulation of signal transduction was suggested to play the crucial role in MV-induced immunosuppression 33 . As PI3K/ Akt pathway is one of the signaling pathways linked to CD150 engagement in lymphocytes 20,22 , we have assumed that MV may also trigger Akt in monocyte-derived human DCs.…”