The immunopathological landscape of human pre-TCRa deficiency: From rare to common variants

Abstract

We describe humans with rare biallelic loss-of-function PTCRA variants impairing pre-a T cell receptor (pre-TCRa) expression. Low circulating naive a|! T cell counts at birth persisted over time, with normal memory a|>, and high T5 T cell counts. Their TCRa repertoire was biased, which suggests that noncanonical thymic differentiation pathways can rescue aft 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 aft T cell counts but high yS T cell counts. Although residual pre-TCRa expression drove the differentiation of more ap T cells, autoimmune conditions were more frequent in these patients compared with the general population. © 2024 American Association for the Advancement of Science. All rights reserved.