Two different forms of inherited human TCRα chain deficiency

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Abstract
Genetic defects that result in the absence of all T cells, including both αβ and γδ T cells, are classified as severe combined immunodeficiency (SCID), a life-threatening condition requiring immediate hematopoietic stem cell transplantation (HSCT) in affected newborns. Previously, patients with a homozygous c.*+1G>A splice variant in the T cell receptor (TCR) α constant chain (TRAC) were found to lack only αβ T cells and demonstrated longer survival compared with SCID patients lacking both αβ and γδ T cells. This observation suggested that γδ T cells might partially compensate for the absence of αβ T cells. Here, we describe two children with biallelic premature stop codons in TRAC. These mutations result in a complete loss of TCRαβ expression on the cell surface and an absence of αβ T cells, leading to severe immunodeficiency and early death. Additionally, we demonstrate that the previously reported c.*+1G>A TRAC variant retains partial activity in vitro, enabling low-level expression of functional TCRαβ. This residual expression likely explains the milder phenotype and extended survival observed in patients carrying this variant. In conclusion, we clarify the nonredundant role of αβ T cells in humans. Our findings show that complete TCRα deficiency causes a SCID-like clinical presentation, whereas partial TCRα deficiency is associated with milder clinical outcomes and longer survival.
Funding Information
  • St. Giles Foundation
  • Rockefeller University
  • Institut National de la Santé et de la Recherche Médicale
  • Institut des maladies génétiques Imagine
  • Paris Cité University
  • National Center for Research Resources
  • National Institutes of Health (UL1TR001866, R01AI095983)
  • Square Foundation
  • Grandir - Fonds de solidarité pour l’enfance
  • SCOR Corporate Foundation for Science
  • Agence Nationale de la Recherche (ANR-10-IAHU-01, ANR-10-LABX-62-IBEID, ANR-21-CE15-0034, ANR-24-CE15-5334)
  • Robert Debré Association for Medical Research
  • General Atlantic Foundation
  • Fondation Bettencourt Schueller
  • itmo cancer of aviesan
  • Institut National Du Cancer

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