Epithelial and dendritic cells in the thymic medulla promote CD4+Foxp3+ regulatory T cell development via the CD27-CD70 pathway

Research output: Contribution to journalJournal articleResearchpeer-review

  • Coquet, Jonathan
  • Julie C Ribot
  • Nikolina Bąbała
  • Sabine Middendorp
  • Gerda van der Horst
  • Yanling Xiao
  • Joana F Neves
  • Diogo Fonseca-Pereira
  • Heinz Jacobs
  • Daniel J Pennington
  • Bruno Silva-Santos
  • Jannie Borst

CD4(+)Foxp3(+) regulatory T cells (Treg cells) are largely autoreactive yet escape clonal deletion in the thymus. We demonstrate here that CD27-CD70 co-stimulation in the thymus rescues developing Treg cells from apoptosis and thereby promotes Treg cell generation. Genetic ablation of CD27 or its ligand CD70 reduced Treg cell numbers in the thymus and peripheral lymphoid organs, whereas it did not alter conventional CD4(+)Foxp3(-) T cell numbers. The CD27-CD70 pathway was not required for pre-Treg cell generation, Foxp3 induction, or mature Treg cell function. Rather, CD27 signaling enhanced positive selection of Treg cells within the thymus in a cell-intrinsic manner. CD27 signals promoted the survival of thymic Treg cells by inhibiting the mitochondrial apoptosis pathway. CD70 was expressed on Aire(-) and Aire(+) medullary thymic epithelial cells (mTECs) and on dendritic cells (DCs) in the thymic medulla. CD70 on both mTECs and DCs contributed to Treg cell development as shown in BM chimera experiments with CD70-deficient mice. In vitro experiments indicated that CD70 on the CD8α(+) subset of thymic DCs promoted Treg cell development. Our data suggest that mTECs and DCs form dedicated niches in the thymic medulla, in which CD27-CD70 co-stimulation rescues developing Treg cells from apoptosis, subsequent to Foxp3 induction by TCR and CD28 signals.

Original languageEnglish
JournalThe Journal of Experimental Medicine
Issue number4
Pages (from-to)715-28
Number of pages14
Publication statusPublished - 8 Apr 2013

    Research areas

  • Animals, Bone Marrow Transplantation, CD27 Ligand/genetics, CD8 Antigens/genetics, Cell Survival/genetics, Dendritic Cells/cytology, Epithelial Cells/cytology, Forkhead Transcription Factors/genetics, Mice, Mice, Knockout, Precursor Cells, T-Lymphoid/cytology, Signal Transduction/physiology, T-Lymphocytes, Regulatory/cytology, Thymus Gland/cytology, Transcription Factors/genetics, Transplantation Chimera/genetics, Transplantation, Homologous, Tumor Necrosis Factor Receptor Superfamily, Member 7/genetics

ID: 356969066