Epithelial and dendritic cells in the thymic medulla promote CD4+Foxp3+ regulatory T cell development via the CD27-CD70 pathway
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Epithelial and dendritic cells in the thymic medulla promote CD4+Foxp3+ regulatory T cell development via the CD27-CD70 pathway. / Coquet, Jonathan M; Ribot, Julie C; Bąbała, Nikolina; Middendorp, Sabine; van der Horst, Gerda; Xiao, Yanling; Neves, Joana F; Fonseca-Pereira, Diogo; Jacobs, Heinz; Pennington, Daniel J; Silva-Santos, Bruno; Borst, Jannie.
In: The Journal of Experimental Medicine, Vol. 210, No. 4, 08.04.2013, p. 715-28.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Epithelial and dendritic cells in the thymic medulla promote CD4+Foxp3+ regulatory T cell development via the CD27-CD70 pathway
AU - Coquet, Jonathan M
AU - Ribot, Julie C
AU - Bąbała, Nikolina
AU - Middendorp, Sabine
AU - van der Horst, Gerda
AU - Xiao, Yanling
AU - Neves, Joana F
AU - Fonseca-Pereira, Diogo
AU - Jacobs, Heinz
AU - Pennington, Daniel J
AU - Silva-Santos, Bruno
AU - Borst, Jannie
PY - 2013/4/8
Y1 - 2013/4/8
N2 - 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.
AB - 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.
KW - Animals
KW - Bone Marrow Transplantation
KW - CD27 Ligand/genetics
KW - CD8 Antigens/genetics
KW - Cell Survival/genetics
KW - Dendritic Cells/cytology
KW - Epithelial Cells/cytology
KW - Forkhead Transcription Factors/genetics
KW - Mice
KW - Mice, Knockout
KW - Precursor Cells, T-Lymphoid/cytology
KW - Signal Transduction/physiology
KW - T-Lymphocytes, Regulatory/cytology
KW - Thymus Gland/cytology
KW - Transcription Factors/genetics
KW - Transplantation Chimera/genetics
KW - Transplantation, Homologous
KW - Tumor Necrosis Factor Receptor Superfamily, Member 7/genetics
U2 - 10.1084/jem.20112061
DO - 10.1084/jem.20112061
M3 - Journal article
C2 - 23547099
VL - 210
SP - 715
EP - 728
JO - The Journal of Experimental Medicine
JF - The Journal of Experimental Medicine
SN - 0022-1007
IS - 4
ER -
ID: 356969066