Immunological Synapse

The immunological synapse is a specialised cell-cell adhesion site between activated T-cells and antigen-presenting cells (Tseng and Dustin 2002). Activation of the T-cell receptor induces activation and recruitment of several tyrosine kinases including ZAP70, Lck and Fyn. The phosphorylation and subsequent recruitment of the Fyb/SLAP/ADAP, Slp-76, LAT and Nck adapter molecules results in the assembly of a protein complex that also includes WASP and Ena/VASP proteins at the immunological synapse (Jordan et al. 2003; Krause et al. 2000). Fyb/SLAP/ ADAP is a haematopoietic-specific adapter molecule that harbours an FP4 motif that directly interacts with Ena/VASP proteins. Importantly, recruitment of both Arp2/3 complex, presumably through WASP, and Ena/VASP proteins was required for the induction of actin polymerization at the T-cell/anti-CD3-coated bead interface, mimicking antigen-presenting cells (Krause et al. 2000). Similarly, the bacterial pathogen Listeria monocytogenes requires the recruitment of both Ena/VASP and the Arp2/3 complex to its ActA surface protein for actin polymerization and efficient intracellular motility (Frischknecht and Way 2001). This showed for the first time that in mammalian cells both Ena/VASP and Arp2/3 are required for efficient actin polymerisation downstream of a cell surface receptor (Krause et al. 2000). In contrast to the bacterial protein ActA, the recruitment of Ena/VASP and Arp2/3 is mediated through the assembly of a protein complex, which allows spatial and temporal regulation. Obviously, this is not essential for Listeria, which requires the constitutive induction of actin polymerization for its own motility, cell-to-cell spread and pathogenicity.

Fyb/SLAP/ADAP knockout T-cells showed impaired proliferation and cytokine production in response to T-cell receptor stimulation. T-cell receptor stimulation is coupled to an increase in integrin-dependent adhesion. Fyb/SLAP/ADAP knockout T-cells are defective in this response, indicating that this protein may couple TCR stimulation to integrin activation and increased adhesion. Surprisingly, actin polymerization at the T-cell antigen-presenting cell contact site was not defective (Griffiths et al. 2001; Peterson et al. 2001). However, Ena/VASP proteins may be recruited in Fyb/SLAP/ADAP KO T-cells to the immunological synapse through RIAM (Lafuente et al. 2004). Whether RIAM is part of the protein complex downstream of the T-cell receptor is currently not known. Interestingly, RIAM overexpression in Jurkat T-cells led to increased adhesion and integrin activation. This suggests that both RIAM and Fyb/SLAP/ADAP may be required for Ena/VASP recruitment to the immunological synapse and for the activation of integrins downstream of the T-cell receptor.

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