Figure 10. Potential consequences of I-A^g7 being endowed with a switch that modulates TCR affinity.

TCRs are selected normally in the thymus against I-A^g7 peptide complexes and the encounter of TCR with an Asp/Glu-containing CDR3β region with a neutral P9 peptide leads to negative selection. However, a small fraction of those same TCRs will be positively selected against pMHC with an Asp/Glu P9 peptide and migrate out of the thymus. In the periphery, normal recognition will occur in a majority of cases, followed by a normal burst of proliferation after recognition of pMHC (scenario no. 1). The exception (scenario no. 2) will happen when a TCR with an Asp/Glu-containing CDR3β detects a pMHC complex displaying a neutral P9 residue; in that instance, increased affinity will lessen pMHC and coreceptor threshold for activation and lead to increased expansion and potentially increased cytokine secretion.