Life and death in the thymus--cell death signaling during T cell development

Abstract

The thymus is an organ vital to proper T cell development, and the regulation of cell survival and death contributes significantly to its efficient function. Vital to many of the developmental processes that occur in the thymus, control over cell survival and death is orchestrated by several signaling processes. In this review, we focus on the regulation of death in early thymocytes known as CD4/CD8 double negative cells, including the roles of interleukin-7 and Bcl-2 family members in this developmental stage. We next consider the survival and death of later thymocytes that express both CD4 and CD8, the 'double-positive' thymocytes. These findings are discussed within the context of recent studies demonstrating the existence of caspase-independent cell death pathways.

Figure 1

Development of T cells at the double negative stage. Factors that lead to double negative T cell survival are listed above the cells and factors that lead to cell death are below the cells. The cell-surface phenotype of each subpopulation is shown. The purple boxes indicate gene rearrangements of the TCRβ receptor. The thymic stromal cells are represented in orange. Please see text for more details.

Figure 2

Pathways involved in thymocyte development during the DP stage. The discrimination of MAPK pathways following TCR ligation results in different selection outcomes. Low-avidity TCR interactions with MHC-peptide (not shown) lead to positive selection, dependent on Erk1/2, whereas high-avidity interactions lead to negative selection, dependent on the recruitment of Grb2/Sos and activation of p38 and Jnk. Negative selecting ligands also result in ERK5 and MINK activation. The convergence of these pathways leads to activation of the Nur77 family and Bim death effectors. (Dotted lines represent potential signaling outcomes). Bim antagonizes Bcl-2 to allow Bax and Bak to effect mitochondrial dysfunction, while Nur77 family members have been shown to turn Bcl-2 into an apotosis promoting protein at the mitochondria. Mcl-1 and Bcl-xL antagonize the function of Bax/Bak, but in the absence of TCR signals, cannot protect cells from apoptosis. TRAIL is induced by Nur77, although the role of this DR in thymocyte apoptosis remains to be fully clarified.