Thymic stromal lymphopoietin-activated plasmacytoid dendritic cells induce the generation of FOXP3+ regulatory T cells in human thymus.
Human thymus contains major dendritic cell (DC) subsets, myeloid DCs (mDCs), and plasmacytoid DCs (pDCs). We previously showed that mDCs, educated by thymic stromal lymphopoietin (TSLP) produced by the epithelial cells of the Hassall's corpuscles, induced differentiation of CD4(+)CD25(-) thymocytes into Forkhead Box P3(+) (FOXP3(+)) regulatory T cells (T(R)) within the medulla of human thymus. In this study, we show that pDCs expressed the TSLP receptor and IL-7 receptor alpha complexes upon activation and became responsive to TSLP. TSLP-activated human pDCs secrete macrophage-derived chemokine CCL-22 and thymus- and activation-regulated chemokine CCL-17 but not Th1- or Th2-polarizing cytokines. TSLP-activated pDCs induced the generation of FOXP3(+) T(R) from CD4(+)CD8(-)CD25(-) thymocytes, which could be strongly inhibited by Th1-polarizing cytokine IL-12 or Th2-polarizing cytokine IL-4. Interestingly, the FOXP3(+) T(R) induced by the TSLP-pDCs expressed more IL-10 but less TGF-beta than that induced by the TSLP-mDCs. These data suggest that TSLP expressed by thymic epithelial cells can activate mDCs and pDCs to positively select the FOXP3(+) T(R) with different cytokine production potential in human thymus. The inability of TSLP to induce DC maturation without producing Th1- or Th2-polarizing cytokines may provide a thymic niche for T(R) development.
Hanabuchi
Shino
S
Department of Immunology and Center for Cancer Immunology Research, University of Texas MD Anderson Cancer Center, Houston, TX 77030-1903, USA.
Ito
Tomoki
T
Park
Woon-Ryon
WR
Watanabe
Norihiko
N
Shaw
Joanne L
JL
Roman
Eulogia
E
Arima
Kazuhiko
K
Wang
Yui-Hsi
YH
Voo
Kui Shin
KS
Cao
Wei
W
Liu
Yong-Jun
YJ
D000328:Adult; D018122:B7-1 Antigen / Q000096:biosynthesis; D051940:B7-2 Antigen / Q000096:biosynthesis; D002454:Cell Differentiation / Q000276:immunology*; D002478:Cells, Cultured; D054414:Chemokine CCL17 / Q000378:metabolism; D054422:Chemokine CCL22 / Q000378:metabolism; D002675:Child, Preschool; D018920:Coculture Techniques; D016207:Cytokines / Q000502:physiology*; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000096:biosynthesis*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D053699:Interleukin-7 Receptor alpha Subunit / Q000096:biosynthesis; D018121:Receptors, Cytokine / Q000096:biosynthesis; D017154:Stromal Cells / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D000094632:Thymic Stromal Lymphopoietin
D018122:B7-1 Antigen; D051940:B7-2 Antigen; C106230:CCL17 protein, human; C515482:CCL22 protein, human; C498762:CRLF2 protein, human; D054414:Chemokine CCL17; D054422:Chemokine CCL22; D016207:Cytokines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D053699:Interleukin-7 Receptor alpha Subunit; D018121:Receptors, Cytokine; D000094632:Thymic Stromal Lymphopoietin