TLR8 escapes X chromosome inactivation in human monocytes and CD4+ T cells

Biology of Sex Differences

Research

Franck J. Barrat¹  Julie Chaumeil²  Berenice Faz-López³  Ali Youness³  Claire Cenac³  Jean-Charles Guéry³  José Enrique Mejía³  Solange Grunenwald⁴ 

[1] Hospital for Special Surgery, HSS Research Institute and David Z. Rosensweig Genomics Research Center, 10021, New York, NY, USA;Department of Microbiology and Immunology, Weill Cornell Medical College of Cornell University, 10021, New York, NY, USA;INSERM, CNRS, Université Paris Cité, Institut Cochin, 75014, Paris, France;Institut Toulousain des Maladies Infectieuses et Inflammatoires (INFINITY), UMR 1291 INSERM, CNRS, Hôpital Purpan, Université de Toulouse, 31024, Toulouse, France;Service d’Endocrinologie, Maladies Métaboliques et Nutrition, Hôpital Larrey, Centre Hospitalier Universitaire (CHU) de Toulouse, 31059, Toulouse, France;

关键词: X chromosome inactivation escape;    Toll-like receptor 8;    Toll-like receptor 7;    Human monocytes and CD4 T cells;    Klinefelter syndrome;   

DOI  :  10.1186/s13293-023-00544-5

 received in 2023-01-19, accepted in 2023-09-04,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundHuman endosomal Toll-like receptors TLR7 and TLR8 recognize self and non-self RNA ligands, and are important mediators of innate immunity and autoimmune pathogenesis. TLR7 and TLR8 are, respectively, encoded by adjacent X-linked genes. We previously established that TLR7 evades X chromosome inactivation (XCI) in female immune cells. Whether TLR8 also evades XCI, however, has not yet been explored.MethodIn the current study, we used RNA fluorescence in situ hybridization (RNA FISH) to directly visualize, on a single-cell basis, primary transcripts of TLR7 and TLR8 relative to X chromosome territories in CD14+ monocytes and CD4+ T lymphocytes from women, Klinefelter syndrome (KS) men, and euploid men. To assign X chromosome territories in cells lacking robust expression of a XIST compartment, we designed probes specific for X-linked genes that do not escape XCI and therefore robustly label the active X chromosome. We also assessed whether XCI escape of TLR8 was associated with sexual dimorphism in TLR8 protein expression by western blot and flow cytometry.ResultsUsing RNA FISH, we show that TLR8, like TLR7, evades XCI in immune cells, and that cells harboring simultaneously TLR7 and TLR8 transcript foci are more frequent in women and KS men than in euploid men, resulting in a sevenfold difference in frequency. This transcriptional bias was again observable when comparing the single X of XY males with the active X of cells from females or KS males. Interestingly, TLR8 protein expression was significantly higher in female mononuclear blood cells, including all monocyte subsets, than in male cells.ConclusionsTLR8, mirroring TLR7, escapes XCI in human monocytes and CD4+ T cells. Co-dependent transcription from the active X chromosome and escape from XCI could both contribute to higher TLR8 protein abundance in female cells, which may have implications for the response to viruses and bacteria, and the risk of developing inflammatory and autoimmune diseases.

【 授权许可】

CC BY   
© Society for Women's Health Research and BioMed Central Ltd. 2023

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