Thymocytes trigger self-antigen-controlling pathways in immature medullary thymic epithelial stages

eLife

Pierre Ferrier¹  Jérémy C Santamaria¹  Magali Irla¹  Noella Lopes¹  Nicolas Boucherit¹  Jonathan Charaix¹  Matthieu Giraud²  Nathan Provin² 

[1] Aix-Marseille University, CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy, Marseille, France;Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes, France;

关键词: thymus;    tolerance;    medullary thymic epithelial cells;    cellular crosstalk;    T cells;   

DOI  :  10.7554/eLife.69982

来源: DOAJ

【 摘 要 】

Interactions of developing T cells with Aire+ medullary thymic epithelial cells expressing high levels of MHCII molecules (mTEChi) are critical for the induction of central tolerance in the thymus. In turn, thymocytes regulate the cellularity of Aire+ mTEChi. However, it remains unknown whether thymocytes control the precursors of Aire+ mTEChi that are contained in mTEClo cells or other mTEClo subsets that have recently been delineated by single-cell transcriptomic analyses. Here, using three distinct transgenic mouse models, in which antigen presentation between mTECs and CD4+ thymocytes is perturbed, we show by high-throughput RNA-seq that self-reactive CD4+ thymocytes induce key transcriptional regulators in mTEClo and control the composition of mTEClo subsets, including Aire+ mTEChi precursors, post-Aire and tuft-like mTECs. Furthermore, these interactions upregulate the expression of tissue-restricted self-antigens, cytokines, chemokines, and adhesion molecules important for T-cell development. This gene activation program induced in mTEClo is combined with a global increase of the active H3K4me3 histone mark. Finally, we demonstrate that these self-reactive interactions between CD4+ thymocytes and mTECs critically prevent multiorgan autoimmunity. Our genome-wide study thus reveals that self-reactive CD4+ thymocytes control multiple unsuspected facets from immature stages of mTECs, which determines their heterogeneity.

【 授权许可】

Unknown