Stomatin-Like Protein 2 Sustains Signalling from T Cell Receptor Signalosomes (87.36)

Abstract T cell activation involves the formation of an organized interface between the T cell and the antigen-presenting cell known as the immunological synapse (IS). Sustained T cell signalling at the IS emanates from peripheral supramolecular activating complexes (pSMACs). We hypothesized that a molecular machinery would anchor the TCR microclusters in the periphery of the synapse to the cytoskeleton allowing the recruitment of signalosome components and providing sustained TCR signalling. Here, we report that stomatin-like protein-2 (SLP-2) is a key element of this machinery by linking the components of the pSMACs to the actin cytoskeleton. SLP-2 is expressed at low levels in resting human lymphocytes but is rapidly up-regulated upon activation. In T cells, SLP-2 polarizes to the IS and actively accumulates in the pSMACs, within lipid rafts. SLP-2 sequentially associates with CD3-ε, Lck, ZAP-70, phospho-LAT and phospho-PLC-γ1, as well as with polymerized actin. In vivo, SLP-2 expression can be detected in areas of lymphocyte activation in human lymph nodes and thymi. Consistent with these data, up-regulation of SLP-2 in T cells correlates with enhanced activation, whereas knocking-down SLP-2 expression in human effector T cells correlates with loss of sustained TCR signalling and down-regulation of effector responses.