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

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  • Additional Information
    • Source:
      Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 0404511 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1095-9203 (Electronic) Linking ISSN: 00368075 NLM ISO Abbreviation: Science Subsets: MEDLINE
    • Publication Information:
      Publication: : Washington, DC : American Association for the Advancement of Science
      Original Publication: New York, N.Y. : [s.n.] 1880-
    • Subject Terms:
      Autoimmunity*/genetics ; Intraepithelial Lymphocytes*/immunology ; Receptors, Antigen, T-Cell, alpha-beta*/genetics ; Membrane Glycoproteins*/genetics; Humans ; Cell Differentiation ; Homozygote ; Loss of Function Mutation ; Lymphocyte Count ; Alleles ; Infections/immunology ; Lymphoproliferative Disorders/immunology ; Pedigree ; Male ; Female ; Middle Aged ; Aged ; Aged, 80 and over
    • 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.
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    • Grant Information:
      UL1 TR001866 United States TR NCATS NIH HHS; ZIA AI001222 United States ImNIH Intramural NIH HHS; K08 AI135091 United States AI NIAID NIH HHS; R01 DK127044 United States DK NIDDK NIH HHS; United States HHMI Howard Hughes Medical Institute
    • Accession Number:
      0 (Receptors, Antigen, T-Cell, alpha-beta)
      0 (pre-T cell receptor alpha)
      0 (Membrane Glycoproteins)
    • Publication Date:
      Date Created: 20240229 Date Completed: 20240304 Latest Revision: 20240617
    • Publication Date:
      20240617
    • Accession Number:
      PMC10958617
    • Accession Number:
      10.1126/science.adh4059
    • Accession Number:
      38422122