Deciphering a genetic control of Human Thymopoiesis at the TCRA-TCRD Locus (Hu-Thy-L) – Hu-Thy-L

The Hu-Thy-L project aims to unravel how genetic variation impacts on chromatin accessibility, epigenetic modifications and/or transcription factors binding, leading to differences in thymocyte differentiation. The understanding of a “fine tuning” of thymopoiesis may improve our basic knowledge of human T cell development with a broad impact in the setting of immune responses and vaccines. It could also provide an insight into the mechanisms of oncogenic translocation in T acute lymphocytic leukemias.

The thymus is the primary organ responsible for the generation of conventional T cells (aß T cells) as well as unconventional T cells including gd T cells and invariant NKT. In a population immunology approach, we characterized the variability of thymic function among 1,000 healthy adults of the Milieu Intérieur cohort. GWAS revealed an association between thymopoiesis and a common variant within the T-cell receptor TCRA-TCRD locus, between the DD2 and DD3 gene segments in a region where TCR rearrangements start in early thymic progenitors. This region is also involved in TCRD-oncogene rearrangements that occur during early thymopoiesis. The aim of the Hu-Thy-L project is to unravel how this genetic variation could be associated with differences in chromatin accessibility, epigenetic changes and/or transcription factors binding, leading to differences in thymocyte differentiation. The understanding of a “fine tuning” of thymopoiesis may improve our basic knowledge of human T cell development with a broad impact in the setting of immune responses. It could also provide an insight into the mechanisms of oncogenic translocation involving the TCRD locus in T-ALL.