Crosstalk between decidual NK and CD14+ myelomonocytic cells results in induction of Tregs and immunosuppression.
Regulatory T cells (Tregs) are thought to play a major role in pregnancy by inhibiting the maternal immune system and preventing fetal rejection. In decidual tissues, NK cells (dNK) reside in close contact with particular myelomonocytic CD14(+) (dCD14(+)) cells. Here we show that the interaction between dNK and dCD14(+) cells results in induction of Tregs. The interaction is mediated by soluble factors as shown by transwell experiments, and the prominent role of IFN-gamma is revealed by the effect of a neutralizing monoclonal antibody. Following interaction with dNK cells, dCD14(+) cells express indoleamine 2,3-dioxygenase (IDO), which, in turn, induces Tregs. Notably, unlike peripheral blood NK (pNK) cells, dNK cells are resistant to inhibition by the IDO metabolite L-kynurenine. "Conditioned" dCD14(+) cells also may induce Tregs through transforming growth factor-beta (TGF-beta) production or CTLA-4-mediated interactions, as indicated by the effect of specific neutralizing Abs. Remarkably, only the interaction between dNK and dCD14(+) cells results in Treg induction, whereas other coculture combinations involving either NK or CD14(+) cells isolated from peripheral blood are ineffective. Our study provides interesting clues to understanding how the crosstalk between decidual NK and CD14(+) cells may initiate a process that leads to Treg induction and immunosuppression. Along this line, it is conceivable that an impaired function of these cells may result in pregnancy failure.
Vacca
Paola
P
Giannina Gaslini Institute, 16147 Genoa, Italy.
Cantoni
Claudia
C
Vitale
Massimo
M
Prato
Carola
C
Canegallo
Francesca
F
Fenoglio
Daniela
D
Ragni
Nicola
N
Moretta
Lorenzo
L
Mingari
Maria Cristina
MC
D015703:Antigens, CD / Q000378:metabolism; D001483:Base Sequence; D060908:CTLA-4 Antigen; D002450:Cell Communication / Q000276:immunology; D017931:DNA Primers / Q000235:genetics; D003656:Decidua / Q000166:cytology* / Q000276:immunology*; D005260:Female; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D066298:In Vitro Techniques; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D007737:Kynurenine / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D022423:Myeloid Cells / Q000276:immunology* / Q000378:metabolism; D011247:Pregnancy / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014364:Tryptophan / Q000378:metabolism
D015703:Antigens, CD; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D017931:DNA Primers; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D018950:Lipopolysaccharide Receptors; D016212:Transforming Growth Factor beta; D007737:Kynurenine; D007371:Interferon-gamma; D014364:Tryptophan