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

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 locus, between the and 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.

Evaluating Thymic Function After Human Hematopoietic Stem Cell Transplantation in the Personalized Medicine Era

“…It has been postulated that thymic mass decreases by an annual rate of 3% until middle age, and subsequently by 1% per year ( 38 ). In the same way, recent data have described that sjTREC values present a decrease of about 4–5% per year ( 26 ), resulting in the subsequent reduction in of naïve T-cell counts. During involution, adipose tissue gradually replaces thymic stromal cells resulting in shrinkage in its size and progressive reduction in thymopoiesis, as shown in mice ( 39 ).…”

“…Since the TCRδ locus is inserted within the TCRα locus, recombination of TCRα entails deletion of the TCRδ segment at a specific site that is common for ~70% of thymocytes, resulting in δRec-ΨJα signal joint TRECs (sjTREC) and coding joint (cjTREC) ( 24 , 25 ) ( Figure 2A ). sjTREC values reflect the thymic output of newly generated T cells and present a strong positive correlation with naïve CD4+, CD8+, and regulatory Tcells ( 26 ). Douek et al ( 25 ) initially introduced TRECs as a reliable surrogate marker for thymic output in the context of HIV infection.…”

Blueprint of human thymopoiesis reveals molecular mechanisms of stage-specific TCR enhancer activation

“…Overall, these epigenomic resources provide a detailed molecular framework to guide future studies on early T cell differentiation in human and their potential implications in leukemogenesis as well as thymic origins of immune-related disorders (Clave et al, 2018;Kernfeld et al, 2018). Abbreviations: DJ, incomplete TCRB rearrangements; GL, germline (TCRB not rearranged); HD, homeodomain gene (i.e., HOXA, TLX1, TLX3).…”

“…Despite numerous reports on the dynamics of epigenetic modifications during murine T cell differentiation (Pekowska et al, 2011;Zhang et al, 2012;Hu et al, 2018;Wei et al, 2011), we still have a limited understanding of the epigenetic mechanisms controlling human T cell differentiation. Thus, describing these mechanisms is of crucial importance, given the potential relevance for immune-related diseases (Clave et al, 2018;Kernfeld et al, 2018) as well as for the oncogenic transformation of T cell precursors (Aifantis et al, 2008).…”

HMGB1 Promotes Myeloid Egress and Limits Lymphatic Clearance of Malignant Pleural Effusions

“…These findings suggest that HMGB1 release may be associated with induction of an antigen-specific γδ T cell response, or alternatively, that aberrant release of DAMPs liberates yet unidentified molecular antigens driving the recruitment of specific γδ T cell populations. The early recruitment of such cells to tissues such as the skin, lung, and gut is in part for them to regulate lymphatic fluid flux and clearance of DAMPs, pathogens and cancer (39)(40)(41)(42)(43). Notably, decreased T cell diversity, primarily within the αβ T cell population, has been identified in the setting of cancer (44)(45)(46).…”