Christiaan N. Levelt

Receptors and signals in early thymic selection

During differentiation, thymocytes are selected twice for expressing a functional version of the CD3-T cell receptor (TCR). A first round of selection involves the immature CD4CD6double-negative (DN) ceils that express interleukin-2 receptor-a (IL-2Ra). At this stage, thymocytes rearrange their TCRj3 genes in a random fashion (Godfrey et al., 1993) leading to a successful rearrangement in approximately 5 of 9 cells (i.e., 56%). Thymocytes that productively rearranged the TCR8 locus are selected by virtue of expressing an immature form of the CD3-TCR, termed pre-TCR, to proliferate, down-regulate IL-2Ra and mature to the CD4+CD8+ double-positive (DP) stage (Groettrup and von Boehmer, 1993; Levelt and Eichmann, 1993). At the same time, TCR8 locus rearrangement is arrested to achieve allelic exclusion. A second round of selection takes place during the DP stage. At this stage, the TCRa genes are rearranged (Petrie et al., 1993) and thymocytes are subsequently subjected to repertoire selection based on the specificity of the mature a+j3+CD3 TCR (Kisielow et al., 1988). DP thymocytes that are positively selected develop into mature CD4+ or CD8+ singlepositive (SP) thymocytes (Chan et al., 1993; Davis et al., 1993). This review deals with the first round of selection in Tcell development: selection for functional rearrangement and expression of the TCR6 chain. The important role of the TCR8 chain in thymic development has been brought out first by studies on mice carrying a functionally rearranged TCR8 transgene (von Boehmer, 1990). In normal mice, the TCR8 transgene arrested the rearrangement of the endogenous TCRj3 gene loci, reflecting the process of allelic exclusion (Uematsu et al., 1988). In Scid mice (Schuler et al., 1986) in which thymocyte development is arrested at the DN IL-2Ra+ stage (Habu et al., 1987; Shoreset al., 1990) aTCR5 transgene restored maturation of thymocytes to the DP stage (von Boehmer, 1990). The pivotal role of the TCR8 chain in early T cell development was further corroborated by the phenotypes of several mutant mouse strains: In mice that cannot produce a TCR8 chain because of a deficiency in the rearrangement machinery (RAG7or RAG2deficient mice) (Mombaerts et al., 1992a; Shinkai et al., 1992a) or because of a mutation in the TCRj3 chain itself (Mombaerts et al., 1992b), thymocyte development is blocked at the DN stage. Introduction of aTCR8 transgene in any of these mice restores T cell maturation to the DP stage (Mombaerts et al., 1992b; Shinkai et al., 1992b). In contrast with TCR8deficient mice, the thymus of TCRa-deficient mice contains normal numbers of DP thymocytes (Philpott et Review