The Standard Model of T‐Cell Receptor Function: A Critical Reassessment

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Abstract
The Standard Model of T‐cell receptor (TCR) function is the distillation of many views. Here we provide a summary that is intended to capture the flavour of the whole, without assigning particular blame, or credit, to any one part. The Standard Model is based on the notion of a single TCR‐combining site that sums the binding contributions of MHC and peptide to produce a single signal to the T cell. How this signal is interpreted can vary with the state of the T cell. A growing number of creaks in the tweaks needed to maintain the Standard Model suggest that it may be timely to make a critical reassessment of the facts and their interpretation. The result of this effort has been to uncover a long‐overlooked fact that T cells do not recognize hybrid class II major histocompatibility complex alleles; they recognize only those haplotypes directly associated with each α‐ or β‐ subunit of class II. Our attempts to tweak the Standard Model to deal with lack of recognition of hybrid class II alleles led us, by surprise, to a quite different framework with which to view TCR function.