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Semaphorin receptors in the immunological synapse: regulation and measles virus-driven modulation
(2010)
Measles virus (MV) infection causes approximately 164,000 deaths per year worldwide (WHO, 2008). The main cause of death is MV-induced immunosuppression but the underlying mechanisms are not fully understood. It has been suggested that MV renders T cells dysfunctional by disrupting the integrity of actin dynamics while MV infection of dendritic cells results in their inability to sustain T cell activation. During neuronal development, semaphorins (SEMAs), especially SEMA3A, induce a collapse of growing dendrites via the binding to plexin-A1 (plexA1) and its coreceptor neuropilin-1 (NP-1). The collapse results from a disruption of actin dynamics. In this study, the roles of these three molecules were investigated in human immune cells and their possible role in MV induced immunosuppression. The present data have shown that plexA1 is an important component of human immunological synapse (IS). It translocated transiently to the surface of T cells after CD3/28 ligation and accumulated at the stimulatory interface between T cells and DCs (or CD3/28 coated beads). When plexA1 expression was inhibited (RNAi) or its function was disrupted (exogenous blocking or dominant negative expression), T cell expansion was reduced. Upon MV exposure, translocation of plexA1 and NP-1, another important component of IS, towards the stimulatory interface in T cells was abrogated. Moreover, MV infection interfered with plexA1/NP-1 turnover in maturing DCs and promoted early and substantial release of SEMA3A from these cells, particularly in the presence of allogenic T cells. As revealed by scanning electron microscopy, the release of SEMA3A caused a transient loss of actin-based protrusions on T cells. SEMA3A affected chemotactic migration of T cells and DCs, and reduced formation of allogenic DC/T cell conjugates. In conclusion, MV targeted SEMA receptor function both by disrupting their recruitment to the IS and by promoting a premature release of their repulsive ligand, SEMA3A. Both of which could contribute to MV-induced immunosuppression.