hery of nascent immunological synapses (Nolz et al., 2006). HS-1, a lymphocyte-specific cortactin is important for forming lamellipodia (Gomez et al., 2006). EVL, a hematopoietic cell member of the ENA-VASP family, is found at the tips of projections touching the APC (Lambrechts et al., 2000). Activation of these systems is not antigen specific and similar structures are induced during non-antigen specific engagement of adhesion molecule like LFA-1 by ICAM-1 (Smith et al., 2003) and CD2 by CD58 (or CD48 in the mouse) (Kaizuka et al., 2009). In response to TCR signals, the SLP-76 signaling module recruits and activates Vav, an exchange factor for Rac and Cdc42. Rac then activates WAVE2 and Cdc42 activates WASP. Both WAVE2 and WASP activate the Arp2/3 complex to generate branched actin networks. WAVE2 is associated with lamellipodial actin (Nolz et al., 2006), whereas WASP is associated with ventral projections such as podosomes and invadipodia (Carman et al., 2007). Behind the lamellipodium is the lamella, which has also been referred to as a focal zone in migrating T cells (Smith et al., 2005). These zones are rich in adhesion sites and integrin binding adapter talin, which is also a marker of the pSMAC. T cell may arrest migration and form a stable synapse, or alternatively, they may continue to migrate and integrate signals on the move. This rapid migration during antigen recognition contrasts with the stable synapse and has different functional consequences.
Rapid migration during antigen recognition is observed in T-DC interactions in vitro early stages of T cell interaction with low dose agonist stimuli in vivo (Henrickson et al., 2008) and with low potency TCR stimuli (Skokos et al., 2007). There are at least two explanations for these mobile junctions or “kinapses”(Dustin, 2008). Certain chemokinetic signals, such as CCL21 signals, can compete with antigen stop signals (Bromley et al., 2000). The ability of T cells to migrate for some period followed by arrest may relate to signaling thresholds or time dependent down-regulation of CCR7. This gives the T cells flexibility in looking at different amounts of antigen on DCs-a few DCs with high amounts of MHC-peptide can stop T cells whereas many DCs with few antigen can sustain signaling until the T cells resets its sensitivity and can arrest (Henrickson et al., 2008). Weaker MHC-peptide never overcome the chemokinetic signals and continually migrate in DC networks (Skokos et al., 2007). T cells encountering these weaker ligands cannot arrest in the steady state and only integrate signals through kinapses. This mode of signal integration is sufficient to induce an alternative mode of tolerance induction when the antigen is presented on many DCs through scavenger receptor DEC-205. The failure of some weaker self-antigens to stop T cells may contribute the failure of tolerance induction and the development of autoimmuity (Zehn and Bevan, 2006). In autoimmunity the combination of strong innate signals and weak TCR signals can lead to robust responses, although there are differences in the kinetics of T cell release from lymph nodes and fitness of the cells that may limit memory generation autoimmunity (Zehn and Bevan, 2006). Thus, a migrating T cell sensing MHC-peptide complexes at its leading edge can integrate signals and make decisions about tolerance to abundant antigens, but not rare self-antigens.
How do T cells form a synapse? T cells stopped by MHC-peptide complexes remained highly dynamics with prominent cycles of extension and retraction around a pivot point (Dustin et al., 1997; Valitutti et al., 1995a). Studies on planar bilayers reveal what appears to be an early spreading, receptor engagement and contractile process that form the cSMAC over a period of 5 minutes and which is F-actin dependent (Grakoui et al., 1999). These results also led to speculation that myosin II based contraction might also be involved because of the substantial decreases in contact size and the speed of receptor cluster movement (Dustin and Cooper, 2000; Grakoui et al., 1999). Simila