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Human thymopoiesis is influenced by a common genetic variant within the TCRA-TCRD locus.
- Source :
- Science Translational Medicine; 9/5/2018, Vol. 10 Issue 457, p1-N.PAG, 11p
- Publication Year :
- 2018
-
Abstract
- Aging, sex, and genetics substantially affect human thymic function. Mining the Milieu Intérieur: Personalized medicine partly depends on understanding what causes variance even outside the context of overt disease. The Milieu Intérieur Consortium enrolled 1000 healthy adults to study how genetics and the environment influence the immune system. Clave et al. leveraged samples from this cohort to see how thymic output, known to decrease over time, is affected by other factors. In addition to seeing sex-dependent differences, a genome-wide association study revealed variants that were associated with thymic output, which was confirmed in an independent cohort and mouse models. The authors have also developed a Web application for other investigators to examine the Milieu Intérieur data. 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. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 19466234
- Volume :
- 10
- Issue :
- 457
- Database :
- Complementary Index
- Journal :
- Science Translational Medicine
- Publication Type :
- Academic Journal
- Accession number :
- 131541584
- Full Text :
- https://doi.org/10.1126/scitranslmed.aao2966