The tuning of T cell antigen receptor (TCR) responsiveness allows immature thymocytes to be positively selected by complexes of self peptide and major histocompatibility complex molecules of lower affinity but prevents mature T cells from responding to similar complexes in the periphery. In the Proceedings of the National Academy of Science, Laufer and colleagues show the kinase Lck redistributes in 'tuned' thymocytes to increase the threshold required for the activation of mature T cells. Tuning occurs in a major histocompatibility complex–dependent manner after positive selection to downregulate TCR sensitivity. In 'untuned' or preselection CD4+CD8+ double-positive thymocytes, more phosphorylated Lck is associated with the TCR CD3ζ chain. In contrast, more Lck associates with CD4 in 'tuned' thymocytes, and these complexes localize in membrane-associated protein islands separate from CD3ζ. This separation of protein islands in 'tuned' cells increases the threshold for TCR activation and thus requires agonist peptides of higher affinity, which thereby lessens the potential for T cell autoreactivity.

Proc. Natl. Acad. Sci. USA (23 April 2012) doi:10.1073/pnas.1119272109