TCR Affinity and Signaling during Thymocyte Selection

How the T cell receptor (TCR) can initiate developmental programs resulting in opposing thymocyte fates (survival versus death) is a central question in immunology. Much work supports the idea that the binding strength (affinity) between TCR and self-peptide major histocompatibility complex (pMHC) plays a pivotal role in this fate decision. In thymocytes, weak binding induces survival and further development (positive selection), whereas no binding or strong binding generally leads to death (death by neglect or negative selection, respectively). However, there is growing evidence that strong interactions between the TCR and self-pMHC lead to the positive selection of specific T cell subsets (agonist selection) rather than negative selection. This article provides insight on how TCR affinity for self-pMHC regulates different thymocyte fates and the signaling mediators that orchestrate thymocyte development.