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

Clave, Emmanuel ; Araujo, Itauá Leston ; Alanio, Cécile ; Patin, Etienne ; Bergstedt, Jacob LU ; Urrutia, Alejandra ; Lopez-Lastra, Silvia ; Li, Yan ; Charbit, Bruno and MacPherson, Cameron Ross , et al. (2018) In Science Translational Medicine 10(457).
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,... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Science Translational Medicine
volume
10
issue
457
article number
aao2966
publisher
American Association for the Advancement of Science (AAAS)
external identifiers
  • scopus:85052811429
  • pmid:30185651
ISSN
1946-6234
DOI
10.1126/scitranslmed.aao2966
language
English
LU publication?
yes
id
e1c1e374-98ce-4d47-b1db-f2dd52b7ae4d
date added to LUP
2018-09-25 12:10:13
date last changed
2021-10-06 04:55:37
@article{e1c1e374-98ce-4d47-b1db-f2dd52b7ae4d,
  abstract     = {<p>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.</p>},
  author       = {Clave, Emmanuel and Araujo, Itauá Leston and Alanio, Cécile and Patin, Etienne and Bergstedt, Jacob and Urrutia, Alejandra and Lopez-Lastra, Silvia and Li, Yan and Charbit, Bruno and MacPherson, Cameron Ross and Hasan, Milena and Melo-Lima, Breno Luiz and Douay, Corinne and Saut, Noémie and Germain, Marine and Trégouët, David Alexandre and Morange, Pierre Emmanuel and Fontes, Magnus and Duffy, Darragh and Di Santo, James and Quintana-Murci, Lluis and Albert, Matthew L. and Toubert, Antoine},
  issn         = {1946-6234},
  language     = {eng},
  month        = {09},
  number       = {457},
  publisher    = {American Association for the Advancement of Science (AAAS)},
  series       = {Science Translational Medicine},
  title        = {Human thymopoiesis is influenced by a common genetic variant within the TCRA-TCRD locus},
  url          = {http://dx.doi.org/10.1126/scitranslmed.aao2966},
  doi          = {10.1126/scitranslmed.aao2966},
  volume       = {10},
  year         = {2018},
}