The standard model of T-cell receptor function: a critical reassessment

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 alpha- or beta- 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.