Embryonic trophoblasts induce decidual regulatory T cell differentiation and maternal-fetal tolerance through thymic stromal lymphopoietin instructing dendritic cells.
Physiological pregnancy requires the maternal immune system to recognize and tolerate embryonic Ags. Although multiple mechanisms have been proposed, it is not yet clear how the fetus evades the maternal immune system. In this article, we demonstrate that trophoblast-derived thymic stromal lymphopoietin (TSLP) instructs decidual CD11c(+) dendritic cells (dDCs)with increased costimulatory molecules; MHC class II; and Th2/3-type, but not Th1-type, cytokines. TSLP-activated dDCs induce proliferation and differentiation of decidual CD4(+)CD25(-) T cells into CD4(+)CD25(+)FOXP3(+) regulatory T cells (Tregs) through TGF-β1. TSLP-activated dDC-induced Tregs display immunosuppressive features and express Th2-type cytokines. In addition, decidual CD4(+)CD25(+)FOXP3(+) Tregs promote invasiveness and HLA-G expression of trophoblasts, resulting in preferential production of Th2 cytokines and reduced cytotoxicity in decidual CD56(bright)CD16(-) NK cells. Of interest, decreased TSLP expression and reduced numbers of Tregs were observed at the maternal-fetal interface during miscarriage. Our study identifies a novel feedback loop between embryo-derived trophoblasts and maternal decidual leukocytes, which induces a tolerogenic immune response to ensure a successful pregnancy.
Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics and Gynecology, Institute of Biomedical Sciences, Fudan University Shanghai Medical College, Shanghai 200011, China.
Mei-Rong
MR
Du
Pei-Fen
PF
Guo
Hai-Lan
HL
Piao
Song-Cun
SC
Wang
Chan
C
Sun
Li-Ping
LP
Jin
Yu
Y
Tao
Yan-Hong
YH
Li
Di
D
Zhang
Rui
R
Zhu
Qiang
Q
Fu
Da-Jin
DJ
Li
D000022:Abortion, Spontaneous / Q000378:metabolism; D000328:Adult; D039521:CD11c Antigen / Q000276:immunology; D015704:CD4 Antigens / Q000378:metabolism; D019002:CD56 Antigen / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology / Q000378:metabolism*; D003656:Decidua / Q000166:cytology / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism*; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D000949:Histocompatibility Antigens Class II; D054502:Histocompatibility, Maternal-Fetal / Q000276:immunology*; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology; D011247:Pregnancy; D017452:Receptors, IgG / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism*; D018418:Th2 Cells / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014327:Trophoblasts / Q000276:immunology / Q000378:metabolism; D055815:Young Adult; D000094632:Thymic Stromal Lymphopoietin
D039521:CD11c Antigen; D015704:CD4 Antigens; D019002:CD56 Antigen; D016207:Cytokines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D000949:Histocompatibility Antigens Class II; D053645:Interleukin-2 Receptor alpha Subunit; D017452:Receptors, IgG; D053773:Transforming Growth Factor beta1; D000094632:Thymic Stromal Lymphopoietin