Our work has specifically focused on the interaction of MV-DC with T cells at the level of the IS, which proved to be only short lived and unable to support sustained Ca2+ fluxing 10. The MV gp complex displayed on the MV-DC/T-cell interface essentially, yet not fully determined IS destabilization and thus, other molecules, potentially including SEMA receptors are likely to be involved also. The important role of the plexA1/NP-1 complex in regulating immune functions has been documented because

their ligands determine whether they functionally support (by self-interaction) or rather selleck kinase inhibitor contribute to termination of (by SEMA3A interaction) the IS 22, 23, 44. The importance of the ligand-binding NP-1 in the IS has been established in murine and human systems 32, 45, and we now

confirmed that, similar to the murine system, plexA1 is an important component of IS function (Fig. 1) and redistributes to the interface between learn more human T cells and DC or stimulator beads (Fig. 2). T-cell exposure to MV-affected surface expression levels of neither plexA1 nor NP-1 (which remained very low and, in agreement with previous observations, is not a marker for human Tregs 46). LPS-driven maturation promoted downregulation of these molecules from the DC surface (Fig. 3) which, for NP-1, is in contrast to what has been observed for that induced by proinflammatory cytokines (32 and mafosfamide also own observations, not shown). As DC matured by inflammatory cytokines are effective at stimulating T-cell expansion, it remains unclear as to whether full or partial retention of NP-1 and plexA1 by MV infection are important in MV-induced alterations of DC functions. Given the importance of plexA1 in T-cell activation, our finding that its recruitment to interfaces with stimulator beads is impaired is likely to interfere with IS efficiency as well. The inability of MV-exposed T cells to organize a correct synapse architecture has previously been described by us and the established interference of MV signalling with actin

cytoskeletal dynamics expectedly accounts for aberrant sorting of receptors probably also including plexA1/NP-1 to this structure 18, 47. This could, however, not directly be confirmed in conjugates between MV-DC and T cells because the majority of these is highly unstable 10. In axon guidance, NP-1/SEMA3A signalling modified the growth cone cytoskeleton by causing retraction of filopodia and lamellopodia and localized rearrangement of the actin cytoskeleton 22. Though it has not been directly addressed, interference with cytoskeletal dynamics might also account for the NP-1/SEMA3A-mediated loss of human thymocyte adhesion to thymic epithelial cells or their ECM-driven migration 35.