The biological activity of natural and mutant pTα alleles

beta selection is a major checkpoint in early thymocyte differentiation, mediated by successful expression of the pre-T cell receptor (TCR) comprising the TCR beta chain, CD3 proteins, and a surrogate TCR alpha chain, pT alpha. The mechanism of action of the pre-TCR is unresolved. In humans and mice, the pT alpha gene encodes two RNAs, pT alpha (a), and a substantially truncated form, pT alpha (b). This study shows that both are biologically active in their capacity to rescue multiple thymocyte defects in pT alpha (-/-) mice. Further active alleles of pT alpha include one that lacks both the major ectodomain and much of the long cytoplasmic tail (which is unique among antigen receptor chains), and another in which the cytoplasmic tail is substituted with the short tail of TCR C alpha. Thus, very little of the pT alpha chain is required for function. These data support a hypothesis that the primary role of pT alpha is to stabilize the pre-TCR, and that much of the conserved structure of pT alpha probably plays a critical regulatory role.