The biological activity of natural and mutant pT alpha alleles

beta selection is a major checkpoint in early thymocyte differentiation, me diated by successful expression of the pre-T cell receptor (TCR) comprising the TCR beta chain, CD3 proteins, and a surrogate TCR alpha chain, pT alph a. 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 tru ncated form, pT alpha (b). This study shows that both are biologically acti ve in their capacity to rescue multiple thymocyte defects in pT alpha (-/-) mice. Further active alleles of pT alpha include one that lacks both the m ajor ectodomain and much of the long cytoplasmic tail (which is unique amon g antigen receptor chains), and another in which the cytoplasmic tail is su bstituted with the short tail of TCR C alpha. Thus, very little of the pT a lpha chain is required for function. These data support a hypothesis that t he primary role of pT alpha is to stabilize the pre-TCR, and that much of t he conserved structure of pT alpha probably plays a critical regulatory rol e.