The immunopathological landscape of human pre-TCRα deficiency: From rare to common variants
Authors:
- Marie MaternaMMMarie Materna
- Ottavia M. DelmonteODOttavia M. Delmonte
- Marita BosticardoMBMarita Bosticardo
- Mana MomenilandiMMMana Momenilandi
- Peyton E. ConreyPCPeyton E. Conrey
- Rebecca BellworthyRBRebecca Bellworthy
- Axel CederholmACAxel Cederholm
- Christian A. GanozaCGChristian A. Ganoza
- Samuel DarkoSDSamuel Darko
Open Access
- 1 March 2024
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science
- Vol. 383 (6686) , eadh4059
Abstract
We describe humans with rare biallelic loss-of-function PTCRA variants impairing pre–α T cell receptor (pre-TCRα) expression. Low circulating naive αβ T cell counts at birth persisted over time, with normal memory αβ and high γδ T cell counts. Their TCRα repertoire was biased, which suggests that noncanonical thymic differentiation pathways can rescue αβ 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 αβ T cell counts but high γδ T cell counts. Although residual pre-TCRα expression drove the differentiation of more αβ T cells, autoimmune conditions were more frequent in these patients compared with the general population.Keywords
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