A critical role for the programmed death ligand 1 in fetomaternal tolerance - PubMed (original) (raw)

A critical role for the programmed death ligand 1 in fetomaternal tolerance

Indira Guleria et al. J Exp Med. 2005.

Abstract

Fetal survival during gestation implies that tolerance mechanisms suppress the maternal immune response to paternally inherited alloantigens. Here we show that the inhibitory T cell costimulatory molecule, programmed death ligand 1 (PDL1), has an important role in conferring fetomaternal tolerance in an allogeneic pregnancy model. Blockade of PDL1 signaling during murine pregnancy resulted in increased rejection rates of allogeneic concepti but not syngeneic concepti. Fetal rejection was T cell- but not B cell-dependent because PDL1-specific antibody treatment caused fetal rejection in B cell-deficient but not in RAG-1-deficient females. Blockade of PDL1 also resulted in a significant increase in the frequency of IFN-gamma-producing lymphocytes in response to alloantigen in an ELISPOT assay and higher IFN-gamma levels in placental homogenates by ELISA. Finally, PDL1-deficient females exhibited decreased allogeneic fetal survival rates as compared with littermate and heterozygote controls and showed evidence of expansion of T helper type 1 immune responses in vivo. These results provide the first evidence that PDL1 is involved in fetomaternal tolerance.

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Figures

Figure 1.

Figure 1.

Kinetics of expression of PDL1/PDL2/B7.2 in placenta of CBA mice. Placentas were removed from pregnant CBA (xB6) mice at 10.5, 13.5, and 16.5 dpc, and cryosections were immunostained for PDL1 (A–C), PDL2 (D–F) and B7.2 (G–I) expression. Staining in placentas at 10.5 (A, D, and G), 13.5 (B, E, and H), and 16.5 (C, F, and I) dpc is shown. Reddish-brown staining for PDL1 shown by arrows is in the decidua basalis (db), the layer next to the trophoblastic giant cells (tgc). PDL2 and B7.2 reddish-brown staining depicted by arrows is in the whole decidua (maternal deciduas, md). Magnification is 20 for all sections except section (C), where it is 40 because the staining was faint and difficult to appreciate at 20×.

Figure 2.

Figure 2.

Effect of PDL1/PDL2/B7.2 blockade on resorption of allogeneic concepti. (A) Pregnant CBA (xB6) females were injected i.p. with anti-PDL1, anti-PDL2, and anti-B7.2 antibodies. The percentages of resorbing fetuses at day 13.5 of pregnancy in mice treated with anti-PDL1 (▾, red), anti-PDL2 (♦, blue), and anti-B7.2 (•, organe). Data in unmanipulated control mice (▪, green) and IgG-treated control mice (▴, magenta) are also shown. Data in the anti-PDL1 group are highly significant (P < 0.0001) over other groups. (B) RAG1−/− females on C57BL/6 background were mated with CBA males and subsequently treated with control IgG or anti-PDL1 antibodies. In parallel, C57BL/6 females were mated with CBA males and subsequently treated with either anti-PDL1 mAb or control IgG. Number of embryos resorbing in each group is shown. (▪, green) B6xCBA control; (▴, red) anti-PDL1; (▾, blue) RAG-1−/−B6xCBA control; (♦, pink) anti-PDL1. The lack of effect of anti-PDL1 during syngeneic pregnancy for CBA x CBA matings or B6 x B6 matings are shown in A (▪, blue, control; ▴, pink, anti-PDL1) and B (•, magenta, control; +, red, anti-PDL1), respectively.

Figure 3.

Figure 3.

T cell infiltration and complement deposition in placentas of anti-PDL1–treated CBA females. CBA (xB6) females were treated with anti-PDL1 at predetermined intervals. Animals were killed, and placental sections were stained for T cells (A, B) and complement (D–F). A depicts T cells stained with anti-CD3 mAb (reddish-brown staining as shown by arrows), and C (whole area depicted) shows a site of hemorrhage during fetal rejection in anti-PDL1–treated group. Arrows show complement deposition in the fetal (D) and maternal (E) part of the placenta. Lack of staining by isotype control is shown in B for T cells and in F for complement. Magnification is 20 for all the sections except C, where it is 10 (to show the whole area undergoing hemorrhage).

Figure 4.

Figure 4.

Expansion of Th1 cells in spleen and placenta of anti-PDL1–treated and PDL1-deficient mice. (A) The frequency of IFN-γ–producing cells from splenocytes of anti-PDL1–treated animals was measured by ELISPOT from a mixed leukocyte reaction in which splenocytes (responder cells) from pregnant CBA mice were cultured in the presence of allogeneic (C57BL/6) stimulators (n = 4–6; P < 0.05). (B) The frequency of IFN-γ–producing cells from splenocytes of PDL1-deficient mice was measured by ELISPOT in a similar fashion (n = 4–6 mice per group; P < 0.05 as compared with PDL1+/+ WT littermate controls). (C) IFN-γ was measured in the placental homogenates by ELISA from anti-PDL1–treated mice (n = 7; P < 0.05 compared with control group). (D) IFN-γ in placental homogenates of PDL1-deficient mice is also shown (n = 6–9 mice per group; P < 0.0001 compared with WT PDL1+/+ littermates).

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