Studies of young mice lacking the pre-T cell receptor α-chain (pre-TCRα; encoded by Ptcra) in the mid-1990s suggested that pre-TCRα is crucial for the development of normal numbers of αβ T cells. Thus, humans lacking pre-TCRα would be predicted to have life-threatening immune defects. A study in Science now reports ten individuals with biallelic loss-of-function (LOF) PTCRA variants who have late-onset or no clinical phenotype. These results suggest the existence of a non-canonical differentiation pathway for αβ T cells that is independent of pre-TCRα.

Using an in-house database of more than 25,000 individuals, the authors identified ten patients from seven unrelated families who have biallelic predicted LOF variants of PTCRA isoform A — the most common isoform in thymocytes — involving splice variants, deletions and premature stop codons. These predicted LOF variants were shown to impair PTCRA expression in vitro, and they were unable to restore surface expression of TCRβ or induce expression of the activation marker CD69 in a TCRα-deficient cell line. Surprisingly, however, six of the ten individuals were clinically asymptomatic (ages 2, 2, 4, 7, 8 and 65). The other four (ages 13, 24, 31 and 66) had phenotypes of infection, lymphoproliferation and/or autoimmunity as teenagers or adults.