Serial Triggering Model

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). The 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 ofTCR 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 ofT-cell response.

Regulating the discriminatory response to antigen by T-cell receptor

“…For such a model to work, the ligand needs fast off rates to serially bind large number of receptors. Several computational models and experimental studies have supported the serial triggering model [105][106][107][108][109][110][111]. However, a direct evidence supporting serial triggering model is lacking and none of the data explained the optimal half-life of pMHC: TCR complex required to initiate an effective downstream response.…”

Modification of the antigenicity of cancer cells by conjugates consisting of hyaluronic acid and foreign antigens

“…Compared with tumor antigens, foreign antigens can avoid negative selection because of the “non-self” antigenicity and have high affinity to MHC class I molecules. 11,12 The binding affinity to MHC class I molecules is proportional to the antigenicity of the antigen that they are presenting. Therefore, if proteins with high antigenicity can be internalized into tumor cells, the degraded peptide can easily bind to host MHC class I molecules instead of the intrinsic antigens.…”