Costimulator B7-DC Attenuates Strong Th2 Responses Induced by <i>Nippostrongylus brasiliensis</i>

Ishiwata, Kenji; Watanabe, Naohiro; Guo, Miao; Tomihara, Kei; Brumlik, Michael J.; Yagita, Hideo; Pardoll, Drew M.; Chen, Lieping; Shin, Tahiro

doi:10.4049/jimmunol.0804051

Cited by 39 publications

(44 citation statements)

References 50 publications

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“…We found that PDL2 expression was stably associated with this DC subset (see below), and we will therefore refer to them here as PDL2 + DCs. Interleukin-4 (IL-4) is known to induce PDL2 expression on dendritic cells (Ishiwata et al, 2010). Interestingly, in vitro generation of PDL2 + DCs could be promoted by IL-4 and inhibited by transforming growth factor-β (TGF-β) (see Figure S1 Aavailable online).…”

Section: Resultsmentioning

confidence: 99%

Control of T Helper 2 Responses by Transcription Factor IRF4-Dependent Dendritic Cells

et al. 2013

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SUMMARY CD4+ T cell differentiation is regulated by specialized antigen-presenting cells. Dendritic cells (DCs) produce cytokines that promote naive CD4+ T cell differentiation into T helper 1 (Th1), Th17, and inducible T regulatory (iTreg) cells. However, the initiation of Th2 cell responses remains poorly understood, although it is likely that more than one mechanism might be involved. Here we have defined a specific DC subset that is involved in Th2 cell differentiation in vivo in response to a protease allergen, as well as infection with Nippostrongylus brasiliensis. We have demonstrated that this subset is controlled by the transcription factor interferon regulatory factor 4 (IRF4), which is required for their differentiation and Th2 cell-inducing function. IRF4 is known to control Th2 cell differentiation and Th2 cell-associated suppressing function in Treg cells. Our finding suggests that IRF4 also plays a role in DCs where it controls the initiation of Th2 cell responses.

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Section: Resultsmentioning

confidence: 99%

Control of T Helper 2 Responses by Transcription Factor IRF4-Dependent Dendritic Cells

et al. 2013

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“…This result was similar to the findings of Shin and colleagues who used knockout mice to show that B7-DC enhances the Th1 response. 18,26 In addition, mB7-DC-Fc directly increases the proliferation of CD4 + but not CD8 + T cells. In contrast, mB7-DC-Fc increased tumor-specific CD8 + TILs in tumor bearing vaccinated mice in vivo.…”

Section: Discussionmentioning

confidence: 99%

Fusion Protein of Mutant B7-DC and Fc Enhances the Antitumor Immune Effect of GM-CSF-secreting Whole-cell Vaccine

Kojima¹,

Murata²,

Mekata³

et al. 2014

Journal of Immunotherapy

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Summary B7-DC [also known as programmed death ligand 2 (PD-L2)] is a costimulatory molecule expressed predominantly on dendritic cells (DCs) and macrophages. In addition to its coinhibitory receptor, programmed death receptor 1 (PD-1), evidence suggests that B7-DC interacts with an unidentified costimulatory receptor on T cells. B7-DC mutants with selective binding capacity for the costimulatory receptor may be effective in stimulating antitumor immune responses, while avoiding the inhibitory effects of PD-1. In this study, we concomitantly administered a GM-CSF-secreting whole cell vaccine together with a fusion protein of mutant B7-DC and Fc portion (mB7-DC-Fc), which binds selectively to the costimulatory receptor. This lead to an increased number of tumor antigen-specific cytotoxic T lymphocytes both in the spleen and at the tumor site and complete elimination of established tumors in vivo. In addition, mB7-DC-Fc increased IFN-γ and IL-2 production and decreased IL-4 and IL-10 production in vitro, indicating that mB7-DC-Fc tips the Th1/Th2 balance toward Th1 dominance, which is more favorable for antitumor immunity. Furthermore, mB7-DC-Fc decreased the PD-1 + proportion of CD8 + T cells in vitro and tumor-infiltrating CD8 + T cells in vivo, suggesting that mB7-DC-Fc may maintain tumor-infiltrating CD8 + T cells in a nonexhausted state. In conclusion, mB7-DC-Fc administration during the T-cell priming phase enhances antitumor effects of vaccine by generating more tumor antigen-specific cytotoxic T lymphocytes and leading to their accumulation at the tumor site. We suggest that this combination approach may be a promising strategy for antitumor immunotherapy.

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“…Of note, PD-1 may not be the only receptor for PD-L2. This can be inferred from helminth infection and allergic animal models, showing enhanced disease severity when PD-L2 blocking antibodies were used, but not when PD-1 blocking antibodies were used (47,48). Furthermore, PD-L2 mutants with abolished PD-1 binding capacity could still exert functional effects on T cells from normal and PD-1-deficient mice (49).…”

Section: Discussionmentioning

confidence: 99%

Relationship between expression of PD-L1 and PD-L2 on esophageal squamous cell carcinoma and the antitumor effects of CD8+ T cells

Leng

Qin

et al. 2015

Oncology Reports

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Abstract. The programmed death-1 (PD-1)/programmed death-ligands (PD-Ls) signal pathway has been implicated as a potential immune escape mechanism in several human cancers. However, the studies of PD-1/PD-Ls pathway in esophageal squamous cell carcinoma (ECSS) are not yet sufficient. The current study investigated the expression of PD-L1, PD-L2 and PD-1 in ESCC tissues. The correlations between the expression of these proteins and clinical histopathological parameters were analyzed. Then the stable transfected Ec109 cell lines overexpressing PD-L1/PD-L2 were established by plasmid transfection successfully. Ec109 and CD8 + T cells were co-cultured to analyze the effects of PD-1/PD-Ls signal pathway on the function of CD8 + T cells including proliferation, apoptosis and interferon-γ production. We found that PD-L1-positive patients had significantly poorer prognosis than the negative patients, while their prognosis was not related to PD-L2 expression. The count of PD-1 + TILs (tumor-infiltrating lymphocytes) was negatively correlated with both PD-L1 and PD-L2 expression. In functional studies, we found that PD-1/PD-Ls signal pathway was able to downregulate the function of CD8 + T lymphocyte and its function could be restored by blocking the signal pathway. This indicates that PD-1/PD-Ls may prevent effective antitumor immunity, which provides important evidence to delineate the cellular immune deficiency mechanism in ESCC. Therefore, PD-1/PD-Ls are predicted to become novel targets for ESCC immunotherapy.

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Costimulator B7-DC Attenuates Strong Th2 Responses Induced by Nippostrongylus brasiliensis

Cited by 39 publications

References 50 publications

Control of T Helper 2 Responses by Transcription Factor IRF4-Dependent Dendritic Cells

Control of T Helper 2 Responses by Transcription Factor IRF4-Dependent Dendritic Cells

Fusion Protein of Mutant B7-DC and Fc Enhances the Antitumor Immune Effect of GM-CSF-secreting Whole-cell Vaccine

Relationship between expression of PD-L1 and PD-L2 on esophageal squamous cell carcinoma and the antitumor effects of CD8+ T cells

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