The Biological Activity of Natural and Mutant Ptα Alleles

Abstract

β selection is a major checkpoint in early thymocyte differentiation, mediated by successful expression of the pre-T cell receptor (TCR) comprising the TCRβ chain, CD3 proteins, and a surrogate TCRα chain, pTα. The mechanism of action of the pre-TCR is unresolved. In humans and mice, the pTα gene encodes two RNAs, pTαa, and a substantially truncated form, pTαb. This study shows that both are biologically active in their capacity to rescue multiple thymocyte defects in pTα−/− mice. Further active alleles of pTα 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 Cα. Thus, very little of the pTα chain is required for function. These data support a hypothesis that the primary role of pTα is to stabilize the pre-TCR, and that much of the conserved structure of pTα probably plays a critical regulatory role.