The goal of the project is to define the antigen presentation and T cell recognition mechanismsresponsible for the activation of myelin-specific CD4 T cells in MS. During this funding period, the Pi's labdetermined the crystal structure of the first human autoimmune TCR and identified an unusual TCR bindingtopology. Biochemical studies demonstrated a low affinity interaction of this TCR with its self-peptide/MHCcomplex, consistent with the suboptimal binding mode observed in the structure. Such a suboptimal bindingmode may facilitate escape from tolerance induction in the thymus and periphery because the relevantantigen presenting cells express limiting quantities of self-antigen. Transgenic mice that express this TCRand the human MHC restriction element nevertheless develop spontaneous autoimmunity at a highincidence, indicating that these T cells have recognition/signaling mechanisms that at least partiallycompensate for the altered TCR interaction with self-peptide/MHC. Imaging studies demonstratedsubstantial differences in the organization of immunological synapses formed by two different myelin-specifichuman T cell clones compared to two anti-viral T cell clones.During the next funding period, we will determine how the altered TCR recognition properties affect theformation of immunological synapses and resulting signaling events.
In Aim 1, we will define themechanisms of immunological synapse formation by examining the kinetics of synapse formation, therecruitment of key signaling molecules, the duration of signaling as well as the mechanisms that terminatesignaling by TCR internalization. Our hypothesis is that the suboptimal TCR binding properties delay TCRtransport to the synapse center where TCR is internalized, thus extending the duration of the initially weakeractivation signal.
In Aim 2, we will examine how these changes quantitatively modify the contribution ofparticular signaling pathways in self-reactive versus anti-viral T cells, with the goal of identifying signalingmolecules that are critical for the activation of self-reactive T cells but dispensable for anti-viral T cells.
In Aim 3, we will examine whether tolerance can nevertheless be induced for such T cells by targeted deliveryof the self-peptide via an antibody-peptide fusion protein to lymph node stromal cells specialized inperipheral tolerance.
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