Thymocyte selection in Vav and IRF-1 gene-deficient mice

Abstract

T cells undergo a defined program of phenotypic and genetic changes during differentiation within the thymus. These changes define commitment of T-cell receptor (TCR)γδ and TCRαβ cells and lineage differentiation into CD4+ T helper and CD8+ cytotoxic T cells. T-cell differentiation and selection in the thymus constitute a tightly co-ordinated multistep journey through a network that can be envisaged as a three-dimensional informational highway made up of stromal cells and extracellular matrix molecules. This intrathymic journey is controlled by information exchange, with thymocytes depending on two-way cellular interactions with thymic stromal cells in order to receive essential signals for maturation and selection. Genetic inactivation of surface receptors, signal transduction molecules, and transcription factors using homologous recombination has provided novel insight into the signaling cascades that relay surface receptor engagement to gene transcription and subsequent progression of the developmental program. In this review we discuss molecular mechanisms of T lymphocyte development in mice that harbour genetic mutations in the guanine nucleotide exchange factor Vav and the interferon regulatory transcription factor 1 (IRF-1). We also propose a novel model of T-cell selection based on TCRα chain-directed signals for allelic exclusion and TCRα-based selection for single receptor usage.