The Immunopathological Landscape of Human Pre-Tcrα Deficiency: from Rare to Common Variants.

We describe humans with rare biallelic loss-of-function PTCRA variants impairing pre-alpha T cell receptor (pre-TCR alpha) expression. Low circulating naive alpha beta T cell counts at birth persisted over time, with normal memory alpha beta and high gamma delta T cell counts. Their TCR alpha repertoire was biased, which suggests that noncanonical thymic differentiation pathways can rescue alpha beta T cell development. Only a minority of these individuals were sick, with infection, lymphoproliferation, and/or autoimmunity. We also report that 1 in 4000 individuals from the Middle East and South Asia are homozygous for a common hypomorphic PTCRA variant. They had normal circulating naive alpha beta T cell counts but high gamma delta T cell counts. Although residual pre-TCR alpha expression drove the differentiation of more alpha beta T cells, autoimmune conditions were more frequent in these patients compared with the general population.