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–a T cell receptor (pre-TCRa) expression. Low
circulating naive ab T cell counts at birth persisted over time, with
normal memory ab and high gd T cell counts. Their TCRa repertoire
was biased, which suggests that noncanonical thymic
differentiation pathways can rescue ab 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 ab T cell counts but high gd T cell counts.
Although residual pre-TCRa expression drove the differentiation
of more ab T cells, autoimmune conditions were more frequent in
these patients compared with the general population.