Thymocytes trigger self-antigen-controlling pathways in immature medullary thymic epithelial stages
| Autor: | Noella Lopes, Nicolas Boucherit, Jérémy C Santamaria, Nathan Provin, Jonathan Charaix, Pierre Ferrier, Matthieu Giraud, Magali Irla |
|---|---|
| Přispěvatelé: | Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Transplantation et Immunologie - Center for Research in Transplantation and Translational Immunology (U1064 Inserm - CR2TI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), ANR-19-CE18-0021,RANKLthym,Évaluer le potentiel de RANK ligand pour rétablir des fonctions thymiques efficaces après greffe de moelle osseuse et vieillissement(2019), DUMENIL, Anita |
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
CD4-Positive T-Lymphocytes
Male [SDV]Life Sciences [q-bio] T cells Mice Transgenic Nerve Tissue Proteins Thymus Gland Autoantigens Epithelium General Biochemistry Genetics and Molecular Biology Histones immunology Mice thymus Animals mouse Mice Knockout medullary thymic epithelial cells Thymocytes tolerance General Immunology and Microbiology Gene Expression Profiling General Neuroscience Epithelial Cells cellular crosstalk General Medicine DNA-Binding Proteins Mice Inbred C57BL [SDV] Life Sciences [q-bio] Gene Expression Regulation inflammation Female Signal Transduction |
| Zdroj: | eLife eLife, 2022, 11, ⟨10.7554/eLife.69982⟩ |
| ISSN: | 2050-084X |
| DOI: | 10.7554/eLife.69982⟩ |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|