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B7DC/PDL2 promotes tumor immunity by a PD-1-independent mechanism.

Liu X, Gao JX, Wen J, Yin L, Li O, Zuo T, Gajewski TF, Fu YX, Zheng P, Liu Y - J. Exp. Med. (2003)

Bottom Line: Meanwhile, compelling evidence exists for costimulatory function of both members.Moreover, B7DC binds to PD-1(-/-) cells and enhances T cell killing in a PD-1-independent mechanism.Our results demonstrate a novel pathway for B7DC to promote tumor immunity and may reconcile the apparently contradictory findings on the function of B7DC.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Ohio State University Medical Center, Columbus, OH 43210, USA.

ABSTRACT
B7H1 (PDL1) and B7DC (PDL2) are two new members of the B7 family that can interact with PD-1, a putative negative regulator for immune function. Recent studies have provided evidence for inhibitory functions of both members via PD-1. Meanwhile, compelling evidence exists for costimulatory function of both members. Here we demonstrate that expression of B7DC on the tumor cells promotes CD8 T cell-mediated rejection of tumor cells, at both the induction and effector phase of antitumor immunity. Moreover, B7DC binds to PD-1(-/-) cells and enhances T cell killing in a PD-1-independent mechanism. Our results demonstrate a novel pathway for B7DC to promote tumor immunity and may reconcile the apparently contradictory findings on the function of B7DC.

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B7DC promotes direct, but not cross-, priming of P1A-specific T cells. (a) P1A–H-2Ld–reactive CD8 T cells in the spleen of mice that were immunized with 5 × 106 of one of the four J558 variants. Spleen cells were harvested 4 wk after tumor cell challenge and stained with FITC-labeled anti-CD8 mAb and H-2LdIg loaded with either a control peptide or the P1A peptide. Data shown are gated CD8 T cells with the percent of dimer-binding cells indicated in each panel. (b) Summary of percent of P1A-specific cells among the CD8 T cells. The data shown were the percentages of H-2LdIg–P1A–binding cells after subtracting those of H-2Ld–ctrl peptide binding cells. (c) Expression of tumor antigen P1A among all J558 variants as analyzed by RT-PCR. GAPDH products were used as control for cDNA quality.
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fig2: B7DC promotes direct, but not cross-, priming of P1A-specific T cells. (a) P1A–H-2Ld–reactive CD8 T cells in the spleen of mice that were immunized with 5 × 106 of one of the four J558 variants. Spleen cells were harvested 4 wk after tumor cell challenge and stained with FITC-labeled anti-CD8 mAb and H-2LdIg loaded with either a control peptide or the P1A peptide. Data shown are gated CD8 T cells with the percent of dimer-binding cells indicated in each panel. (b) Summary of percent of P1A-specific cells among the CD8 T cells. The data shown were the percentages of H-2LdIg–P1A–binding cells after subtracting those of H-2Ld–ctrl peptide binding cells. (c) Expression of tumor antigen P1A among all J558 variants as analyzed by RT-PCR. GAPDH products were used as control for cDNA quality.

Mentions: It has been established that a major tumor antigen in the J588 tumor cells is P1A peptide AA35-43 presented by H-2Ld (25). Therefore, we analyzed the number of P1A-reactive T cells in mice challenged with either J558-Neo or J558-B7DC, using H-2Ld dimer loaded with either the P1A peptide or a control H-2Ld–binding peptide. As shown in Fig. 2 , P1A-reactive T cells were barely detectable in mice challenged with the J558-Neo tumor cells. In contrast, the mice that received the J558-B7DC produced high numbers of P1A-reactive CD8 T cells. On average, ∼1% of CD8 T cells in the spleen of the J558-B7DC–primed mice were specific for the P1A peptide, whereas the numbers of antigen-specific T cells were ∼10-fold lower in the mice that were challenged with the J558-Neo tumor cells. Thus, B7DC may deliver a positive signal to enhance immunity in vivo.


B7DC/PDL2 promotes tumor immunity by a PD-1-independent mechanism.

Liu X, Gao JX, Wen J, Yin L, Li O, Zuo T, Gajewski TF, Fu YX, Zheng P, Liu Y - J. Exp. Med. (2003)

B7DC promotes direct, but not cross-, priming of P1A-specific T cells. (a) P1A–H-2Ld–reactive CD8 T cells in the spleen of mice that were immunized with 5 × 106 of one of the four J558 variants. Spleen cells were harvested 4 wk after tumor cell challenge and stained with FITC-labeled anti-CD8 mAb and H-2LdIg loaded with either a control peptide or the P1A peptide. Data shown are gated CD8 T cells with the percent of dimer-binding cells indicated in each panel. (b) Summary of percent of P1A-specific cells among the CD8 T cells. The data shown were the percentages of H-2LdIg–P1A–binding cells after subtracting those of H-2Ld–ctrl peptide binding cells. (c) Expression of tumor antigen P1A among all J558 variants as analyzed by RT-PCR. GAPDH products were used as control for cDNA quality.
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Related In: Results  -  Collection

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fig2: B7DC promotes direct, but not cross-, priming of P1A-specific T cells. (a) P1A–H-2Ld–reactive CD8 T cells in the spleen of mice that were immunized with 5 × 106 of one of the four J558 variants. Spleen cells were harvested 4 wk after tumor cell challenge and stained with FITC-labeled anti-CD8 mAb and H-2LdIg loaded with either a control peptide or the P1A peptide. Data shown are gated CD8 T cells with the percent of dimer-binding cells indicated in each panel. (b) Summary of percent of P1A-specific cells among the CD8 T cells. The data shown were the percentages of H-2LdIg–P1A–binding cells after subtracting those of H-2Ld–ctrl peptide binding cells. (c) Expression of tumor antigen P1A among all J558 variants as analyzed by RT-PCR. GAPDH products were used as control for cDNA quality.
Mentions: It has been established that a major tumor antigen in the J588 tumor cells is P1A peptide AA35-43 presented by H-2Ld (25). Therefore, we analyzed the number of P1A-reactive T cells in mice challenged with either J558-Neo or J558-B7DC, using H-2Ld dimer loaded with either the P1A peptide or a control H-2Ld–binding peptide. As shown in Fig. 2 , P1A-reactive T cells were barely detectable in mice challenged with the J558-Neo tumor cells. In contrast, the mice that received the J558-B7DC produced high numbers of P1A-reactive CD8 T cells. On average, ∼1% of CD8 T cells in the spleen of the J558-B7DC–primed mice were specific for the P1A peptide, whereas the numbers of antigen-specific T cells were ∼10-fold lower in the mice that were challenged with the J558-Neo tumor cells. Thus, B7DC may deliver a positive signal to enhance immunity in vivo.

Bottom Line: Meanwhile, compelling evidence exists for costimulatory function of both members.Moreover, B7DC binds to PD-1(-/-) cells and enhances T cell killing in a PD-1-independent mechanism.Our results demonstrate a novel pathway for B7DC to promote tumor immunity and may reconcile the apparently contradictory findings on the function of B7DC.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Ohio State University Medical Center, Columbus, OH 43210, USA.

ABSTRACT
B7H1 (PDL1) and B7DC (PDL2) are two new members of the B7 family that can interact with PD-1, a putative negative regulator for immune function. Recent studies have provided evidence for inhibitory functions of both members via PD-1. Meanwhile, compelling evidence exists for costimulatory function of both members. Here we demonstrate that expression of B7DC on the tumor cells promotes CD8 T cell-mediated rejection of tumor cells, at both the induction and effector phase of antitumor immunity. Moreover, B7DC binds to PD-1(-/-) cells and enhances T cell killing in a PD-1-independent mechanism. Our results demonstrate a novel pathway for B7DC to promote tumor immunity and may reconcile the apparently contradictory findings on the function of B7DC.

Show MeSH
Related in: MedlinePlus