Commitment issues: linking positive selection signals and lineage diversification in the thymus

Abstract

The thymus is responsible for the production of CD4+ helper and CD8+ cytotoxic T cells, which constitute the cellular arm of the immune system. These cell types derive from common precursors that interact with thymic stroma in a T-cell receptor (TCR)-specific fashion, generating intracellular signals that are translated into function-specific changes in gene expression. This overall process is termed positive selection, but it encompasses a number of temporally distinct and possibly mechanistically distinct cellular changes, including rescue from apoptosis, initiation of cell differentiation, and commitment to the CD4+ or CD8+ T-cell lineage. One of the puzzling features of positive selection is how specificity of the TCR controls lineage commitment, as both helper and cytolytic T cells utilize the same antigen-receptor components, with the exception of the CD4 or CD8 coreceptors themselves. In this review, we focus on the signals required for positive selection, particularly as they relate to lineage commitment. Identification of genes encoding transcriptional regulators that play a role in T-cell development has led to significant recent advances in the field. We also provide an overview of nuclear factors in this context and, where known, how their regulation is linked to the same TCR signals that have been implicated in initiating and regulating positive selection.