T cell selection

Abstract: Understanding how thymic selection imparts self-peptide-MHC complex restriction and a high degree of self tolerance on the T cell repertoire requires a detailed description of the parameters that shape the MHC ligand repertoire of distinct thymic antigen-presenting cells and of how these cells communicate with T cells. Several recent discoveries pertaining to cortex-specific pathways of antigen processing, the heterogeneity of thymic dendritic cells and the intercellular transfer of self antigens have uncovered surprising and unique aspects of antigen presentation in the thymic microenvironment. Here, we discuss these new findings in the context of how individual thymic stromal cell types support T cell selection in a cooperative rather than a redundant manner.

Abstract: Differentiation of early thymocytes into mature T cells depends upon intrathymic T cell contact with major histocompatibility complex (MHC) molecules, i.e., H-2 molecules in mice. T cell recognition of H-2 molecules in the thymus has two consequences. First, some T cells undergo a process of positive selection which leads specifically-reactive immature thymocytes to survive and differentiate into mature functional T cells. Second, T cells with high affinity for H-2 molecules undergo negative selection (tolerance). We and others have argued that positive selection is controlled by thymic epithelial cells, especially cortical epithelium, whereas negative selection reflects contact with bone-marrow (BM) derived cells. This scheme appears to be an oversimplication because we have recently found evidence that a non-BM-derived component of the thymus, presumably epithelial cells, is highly tolerogenic for CD4+ cells. Whether tolerance of CD4+ cells is controlled by cortical epithelium or medullary epithelium is unclear. In this respect it is of interest that chronic injection of mice with cyclosporine A results in selective destruction of medullary epithelial cells and impaired induction of self tolerance.

Abstract: The genetic programs directing CD4 or CD8 T cell differentiation in the thymus remain poorly understood. While analyzing gene expression during intrathymic T cell selection, we found that Zfp67, encoding the zinc finger transcription factor cKrox, was upregulated during the differentiation of CD4(+) but not CD8(+) T cells. Expression of a cKrox transgene impaired CD8 T cell development and caused major histocompatibility complex class I-restricted thymocytes to differentiate into CD4(+) T cells with helper properties rather than into cytotoxic CD8(+) T cells, as normally found. CD4 lineage differentiation mediated by cKrox required its N-terminal BTB (bric-a-brac, tramtrack, broad complex) domain. These findings identify cKrox as a chief CD4 differentiation factor during positive selection.