Gylemo Björn, Bensberg Maike, Hennings Viktoria, Lundqvist Christina, Camponeschi Alessandro, Goldmann Dóra, Zhang Huan, Selimović-Pašić Aida, Lentini Antonio, Ekwall Olov, Nestor Colm E
Crown Princess Victoria Children's Hospital, and Department of Biomedical and Clinical Sciences (BKV), Linköping University, Linköping, Sweden.
Department of Rheumatology and Inflammation Research, Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Nat Commun. 2024 Dec 4;15(1):10527. doi: 10.1038/s41467-024-54110-7.
Females exhibit a more robust immune response to both self-antigens and non-self-antigens than males, resulting in a higher prevalence of autoimmune diseases but more effective responses against infection. Increased expression of X-linked immune genes in female T cells is thought to underlie this enhanced response. Here we isolate thymocytes from pediatric thymi of healthy males (46, XY), females (46, XX), a female with completely skewed X-chromosome inactivation (46, XX, cXCI) and a female with Turner syndrome (45, X0). Using whole exome sequencing, RNA sequencing and DNA methylation data, we present a sex-aware expression profile of T cell development and generate a high-resolution map of escape from X-chromosome inactivation (XCI). Unexpectedly, XCI is transcriptionally and epigenetically stable throughout T cell development, and is independent of expression of XIST, the lncRNA responsible for XCI initiation during early embryonic development. In thymocytes, several genes known to escape XCI are expressed from only one X-chromosome. Additionally, we further reveal that a second X-chromosome is dispensable for T cell development. Our study thus provides a high-resolution map of XCI during human development and suggests a re-evaluation of XCI in sex differences in T cell function.
与男性相比，女性对自身抗原和非自身抗原均表现出更强的免疫反应，这导致自身免疫性疾病的患病率更高，但对感染的反应更有效。女性T细胞中X连锁免疫基因的表达增加被认为是这种增强反应的基础。在这里，我们从健康男性（46, XY）、女性（46, XX）、一名X染色体完全偏态失活的女性（46, XX, cXCI）和一名特纳综合征女性（45, X0）的儿科胸腺中分离出胸腺细胞。利用全外显子组测序、RNA测序和DNA甲基化数据，我们展示了T细胞发育的性别特异性表达谱，并生成了一份从X染色体失活（XCI）逃逸的高分辨率图谱。出乎意料的是，XCI在整个T细胞发育过程中转录和表观遗传上都是稳定的，并且独立于XIST的表达，XIST是一种在早期胚胎发育过程中负责启动XCI的长链非编码RNA。在胸腺细胞中，已知从XCI逃逸的几个基因仅从一条X染色体表达。此外，我们进一步揭示了第二条X染色体对于T细胞发育是可有可无的。因此，我们的研究提供了人类发育过程中XCI的高分辨率图谱，并建议重新评估XCI在T细胞功能性别差异中的作用。
