Molecular Regulation of Early T-Cell Development in the Thymus

textabstractThe human body is under constant siege of pathogens - bacteria, viruses, fungi and parasites. We can only survive because these attackers are continuously fought off by our immune system. Important tasks within the immune system of vertebrates are performed by T lymphocytes, the executors of speci.c, cellular immunity. The speci.city of T lymphocytes lies in their T-cell receptor (TCR), through which they sense the presence of antigens in their environment. Each T cell expresses a TCR with a unique antigen-recognition site, so all T cells together can respond to an enormous variety of antigens. The highly diverse T-cell repertoire is generated by random recombination of discrete TCR gene segments. Via the TCR, T cells recognize peptide antigens that are displayed by antigen presenting cells (APCs), in the context of major histocompatibility complex (MHC) class I or class II molecules. Mature T cells carry out their function in cellular immunity as either CD8+ cytotoxic T cells or as CD4+ helper T cells. The humoral part of the speci.c immune system is supplied by B lymphocytes, which can secrete their antigen receptors in the form of antibodies. T cells develop from multipotent precursors via a highly ordered, but complex differentiation pathway. A number of critical events occur during this T-cell development process. Cells proliferate, adopt a T-cell fate, and produce a TCR molecule via a strictly ordered process of gene rearrangements. Stringent selection processes make sure that the produced TCR molecule is self-MHC restricted but not reactive to self-antigens. Finally, the selected T cells are allowed to mature into functional effector T cells. To become highly differentiated and thoroughly ‘educated’ cells, T cells need a specialized microenvironment for their development. The organ which has evolved to ful.ll this task and which also gave T cells their name, is the Thymus. The hematopoietic cells that undergo T-cell development in the thymus are called thymocytes. The importance of the thymus as essential microenvironment for T-cell development is illustrated by children af.icted by the DiGeorge syndrome, who sometimes completely lack a thymus. These children have severely reduced T cell numbers and suffer from recurrent life-threatening infections. DiGeorge syndrome also illustrates the fact that T cells are the only hematopoietic cell type that absolutely require the thymus for their development. Although human T-cell development is the main theme of this thesis, most of the published knowledge about T-cell differentiation has been acquired by studies in the mouse