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 -