Serial Triggering Model

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Abstract

T-cells recognize a foreign antigen when presented on antigen-presenting cells (APCs) in the context of a peptide bound to major histocompatibility complex (MHC). Ihe recognition of an antigen takes place at the T-cell: APC contact site where an “immune synapse” is formed and the multichain T-cell antigen receptor (TCR) is triggered. This initiates a signal transduction cascade that involves activation of tyrosine kinases, which in turn activate downstream events that elicit a diverse array of effector functions. T-cell activation requires a sustained signal that lasts for several hours. However, TCR affinity to its antigen is low and activation of TCR induces only a brief spike of intracellular signals. The serial triggering model resolves these seemingly paradoxical requirements for T-cell activation. The model states that sustained signaling is accomplished by the concerted action of multiple T-cell receptors that are sequentially engaged with and triggered by the peptide:MHC complex. In this chapter, we review the serial triggering model and two other models that expand this model. These models describe kinetic aspects of T-cell activation such as the pivotal question of how the T-cell “counts” the number of serially triggered receptors over time and how it determines that a threshold level has been reached for the activation of T-cell response.