The Immunopathological Landscape of Human Pre-Tcra Deficiency: From Rare to Common Variants Publisher Pubmed

Summary: T-cell glitch rare? Study finds PTCRA variants cut naive αβ T cells, raise autoimmune risk. Research suggests immune pathway tweaks—health clue? #Immunodeficiency #TCellDevelopment

Materna M^{1, 2} ; Delmonte OM³ ; Bosticardo M³ ; Momenilandi M^{1, 2} ; Conrey PE⁴ ; Muylder BCD⁵ ; Bravetti C^{6, 7} ; Bellworthy R⁸ ; Cederholm A⁹ ; Staels F¹⁰ ; Ganoza CA¹¹ ; Darko S¹² ; Sayed S⁴ ; Floch CL^{1, 2} Show All Authors
Source: Science Published:2024

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.