Early events in T cell development

Abstract: T cells constitute a heterogenous population of lymphocytes. Their unifying property is that they express surface bound antigen-receptors, called T cell receptors (TCRs). The TCR is a heterodimer composed of either TCRalpha and beta chain proteins (alphabeta TCR) or gamma and delta chain proteins (gammadelta TCR). Depending on which TCR isotype that is expressed, the T cells are divided into alphabeta T cells or gammadelta T cells. In contrast to other hematopoietic cells, T cells develop in an organ called the thymus. To become a mature T cell the thymocytes proceed through a differentiation program that is partially induced by the surrounding thymic epithelial cells. T cell development can be divided into an early and a late stage of differentiation. The purpose of the early stage is to provide the developing thymocytes with functional TCRs. This is mediated by rearrangements at the DNA level of the TCRbeta, gamma and delta genes. If the TCRbeta gene is functionally rearranged, it will pair with a protein called pTalpha to form the preTCR complex that assures rearrangements of the TCRalpha genes and differentiation into the alphabeta T cell lineage. On the other hand, if the TCRgamma and delta chain genes are rearranged functionally the thymocyte will deviate from the mainstream alphabeta T cell pathway to become a mature gammadelta T cell. Whereas conventional alphabeta T cell development is quite well understood today, that of unconventional alphabeta T cells and gammadelta T cells is not. This thesis concerns the early stages of T cell development. With the articles herein, we provide information about the role of the TCR and preTCR in alphabeta versus gammadelta T cell development. We have furthermore examined the expression and transcriptional regulation of the pTalpha gene. Together, these findings lead to a better understanding of the early events in T cell development.