Human thymopoiesis is influenced by a common genetic variant within the TCRA-TCRD locus

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

Abstract

The thymus is the primary lymphoid organ where naïve T cells are generated; however, with the exception of age, the parameters that govern its function in healthy humans remain unknown. We characterized the variability of thymic function among 1000 age- and sex-stratified healthy adults of the Milieu Intérieur cohort, using quantification of T cell receptor excision circles (TRECs) in peripheral blood T cells as a surrogate marker of thymopoiesis. Age and sex were the only nonheritable factors identified that affect thymic function. TREC amounts decreased with age and were higher in women compared to men. In addition, a genome-wide association study revealed a common variant (rs2204985) within the T cell receptor TCRA-TCRD locus, between the DD2 and DD3 gene segments, which associated with TREC amounts. Strikingly, transplantation of human hematopoietic stem cells with the rs2204985 GG genotype into immunodeficient mice led to thymopoiesis with higher TRECs, increased thymocyte counts, and a higher TCR repertoire diversity. Our population immunology approach revealed a genetic locus that influences thymopoiesis in healthy adults, with potentially broad implications in precision medicine.

Detaljer

Författare
  • Emmanuel Clave
  • Itauá Leston Araujo
  • Cécile Alanio
  • Etienne Patin
  • Jacob Bergstedt
  • Alejandra Urrutia
  • Silvia Lopez-Lastra
  • Yan Li
  • Bruno Charbit
  • Cameron Ross MacPherson
  • Milena Hasan
  • Breno Luiz Melo-Lima
  • Corinne Douay
  • Noémie Saut
  • Marine Germain
  • David Alexandre Trégouët
  • Pierre Emmanuel Morange
  • Magnus Fontes
  • Darragh Duffy
  • James Di Santo
  • Och 3 andra
  • Lluis Quintana-Murci
  • Matthew L. Albert
  • Antoine Toubert
Enheter & grupper
Externa organisationer
  • Paris Diderot University
  • Pasteur Institute
  • Genentech, Inc
  • La Timone University Hospital
  • Aix-Marseille University
  • Paris-Sorbonne University
  • Institute for Cardiometabolism and Nutrition
  • Saint-Louis Hospital, Paris
  • The Milieu Interieur Consortium
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Immunologi inom det medicinska området
Originalspråkengelska
Artikelnummeraao2966
TidskriftScience Translational Medicine
Volym10
Utgåva nummer457
StatusPublished - 2018 sep 5
PublikationskategoriForskning
Peer review utfördJa