B7-H1 (Programmed Death-1 Ligand) on Dendritic Cells Is Involved in the Induction and Maintenance of T Cell Anergy

Selenko-Gebauer, Nicole; Majdic, Otto; Szekeres, Andreas; Höfler, Gerald; Guthann, Elisabeth; Korthäuer, Ulf; Zlabinger, Gerhard J.; Schmitz, Peter; Pickl, Winfried F.; Stockinger, Hannes; Knapp, Walter; Stöckl, Johannes

doi:10.4049/jimmunol.170.7.3637

Cited by 246 publications

(185 citation statements)

References 30 publications

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“…In line with other studies using tolerogenic DC [11,12], we have previously reported that this model involves the induction of non-deletional tolerance [13].…”

Section: Hyporesponsive T Cells Display Reduced Migratory Ability Andsupporting

confidence: 86%

Tolerant T cells display impaired trafficking ability

et al. 2005

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Based on our previous observation that anergic T lymphocytes lose their migratory ability in vitro, we have proposed that anergic T cells are retained in the site where they have been generated to exert their regulatory function. In this study we have analyzed T lymphocyte trafficking and motility following the induction of tolerance in vivo. In a model of non-deletional negative vaccination to xenoantigens in which dendritic cells (DC) localize to specific lymphoid sites depending on the route of administration, tolerant T cells remained localized in the lymph nodes colonized by tolerogenic DC, while primed T cells could traffic efficiently. Using an oral tolerance model that enables the 'tracking' of ovalbumin-specific TCR-transgenic T cells, we confirmed that T cells lose the ability to migrate through syngeneic endothelial cell monolayers following tolerance induction in vivo. Finally, we show that tolerant T cells (both in vitro and ex vivo) can inhibit migration of responsive T cells in an antigen-independent manner. Thus, hyporesponsive T cells localize at the site of tolerance induction in vivo, where they exert their anti-inflammatory properties. In physiological terms, this effect is likely to render immunoregulation a more efficient and controllable event.

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“…In line with other studies using tolerogenic DC [11,12], we have previously reported that this model involves the induction of non-deletional tolerance [13].…”

Section: Hyporesponsive T Cells Display Reduced Migratory Ability Andsupporting

confidence: 86%

Tolerant T cells display impaired trafficking ability

et al. 2005

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“…25 We and others have shown a strong association between B7-H1 expression and bad prognostic factors in several malignancies. [16][17][18][19]35 In the present study the strong link observed between B7-H1 and Ki-67 markers suggests that the low patients' survival, 25 seen in highly proliferating tumors, may be the results of B7-H1 induction in proliferating tumor cells leading to the inhibition of the immune system [10][11][12]36 and thereby providing more advantages for the tumors to grow.…”

Section: Discussionmentioning

confidence: 86%

“…[9][10][11][12] It has been shown to be directly involved in the protection of cancer cells from activated T lymphocytes. 13 The expression of this molecule has been described in several malignancies including ovary, colon, melanoma and carcinoma of the lung.…”

mentioning

confidence: 99%

Expression of B7‐H1 in breast cancer patients is strongly associated with high proliferative Ki‐67‐expressing tumor cells

Ghebeh¹,

Tulbah²,

Mohammed³

et al. 2007

Intl Journal of Cancer

132

106

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B7-H1, a coinhibitory molecule, plays a role in immune escape of tumors. We have shown previously the expression of this molecule in breast cancer patients and demonstrated its association with high histological grade, progesterone and estrogen receptor negative status, all of which are known to have direct impact on cell proliferation. In the present work, we investigated the effect of proliferation, as measured by Ki-67 and mitotic count, on the induction of B7-H1. We used H&E stained sections to score for mitotic count in 69 breast cancer patients. Immunohistochemistry was used to investigate B7-H1 and Ki-67 expression. The relationship between B7-H1 induction and cell proliferation was further investigated in primary cultured cells. B7-H1 expression was recorded in patients with a high mitotic index (p 5 0.007). There was a high significant correlation between B7-H1 expression and the presence of the proliferative marker Ki-67 (p < 0.001) indicating the association of proliferation with B7-H1 induction. Furthermore, B7-H1 was gradually induced in proliferating cells of 8/8 primary cell lines as measured by Ki-67 expression. Finally, B7-H1 was downregulated in quiescent cells and upregulated in cells stimulated with a mitogen confirming the association of proliferation with the induction of B7-H1. We have shown for the first time a direct association between proliferation and the expression of B7-H1 in breast cancer patients. The relationship between B7-H1 induction and cell proliferation was also thoroughly investigated in vitro, in which a strong link between B7-H1 expression and the presence of the proliferative Ki-67 marker was clearly demonstrated. ' 2007 Wiley-Liss, Inc.Key words: B7-H1; PD-L1; breast cancer; Ki-67; proliferation; mitotic index About 40% of women still die of breast cancer in spite of the significant advances in traditional, targeted and neo-adjuvant therapies. 1 Immunotherapeutic strategies aimed at manipulating the patient's immune system to specifically destroy tumor cells may represent a major alternative approach for the management of cancer. 2,3 However, the presence of an existing immune tolerance in patients with advanced cancer may limit the clinical effectiveness of such therapeutic strategies. 4 Several mechanisms have been attributed to the immune defect seen in breast cancer patients with advanced disease; where a lower number of blood lymphocytes, 5 elevated T regulatory lymphocytes, 6 defective dendritic cells 7 and expression of FasL in breast cancer 8 were described.A T lymphocyte inhibitory molecule named B7-H1 (also called PD-L1) expressed by antigen presenting cells has been shown to induce T lymphocyte anergy and/or apoptosis after ligation to its T lymphocytes receptor PD-1. 9-12 It has been shown to be directly involved in the protection of cancer cells from activated T lymphocytes. 13 The expression of this molecule has been described in several malignancies including ovary, colon, melanoma and carcinoma of the lung. 11 Others includes; squamous cell carcinoma o...

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“…It would be of interest to ascertain whether differences in the level of B7-H1 among anatomically distinct (bone marrow vs spleen) dendritic cells contribute to suboptimal immune responses. B7-H1 expression by dendritic cells has been implicated in the induction and maintenance of T cell anergy and tolerance (35,36). Tumor myeloid dendritic cells express high levels of B7-H1, and the blockade of B7-H1 engagement enhances infiltration of effector CD8 ϩ T cells, thereby conferring improved antitumor immunity (37).…”

Section: Discussionmentioning

confidence: 99%

Targeting Molecular and Cellular Inhibitory Mechanisms for Improvement of Antitumor Memory Responses Reactivated by Tumor Cell Vaccine

Webster¹,

Thompson²,

Harris

et al. 2007

The Journal of Immunology

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Development of effective vaccination approaches to treat established tumors represents a focus of intensive research because such approaches offer the promise of enhancing immune system priming against tumor Ags via restimulation of pre-existing (memory) antitumoral helper and effector immune cells. However, inhibitory mechanisms, which function to limit the recall responses of tumor-specific immunity, remain poorly understood and interfere with therapies anticipated to induce protective immunity. The mouse renal cell carcinoma (RENCA) tumor model was used to investigate variables affecting vaccination outcomes. We demonstrate that although a whole cell irradiated tumor cell vaccine can trigger a functional antitumor memory response in the bone marrows of mice with established tumors, these responses do not culminate in the regression of established tumors. In addition, a CD103+ regulatory T (Treg) cell subset accumulates within the draining lymph nodes of tumor-bearing mice. We also show that B7-H1 (CD274, PD-L1), a negative costimulatory ligand, and CD4+ Treg cells collaborate to impair the recall responses of tumor-specific memory T cells. Specifically, mice bearing large established RENCA tumors were treated with tumor cell vaccination in combination with B7-H1 blockade and CD4+ T cell depletion (triple therapy treatment) and monitored for tumor growth and survival. Triple treatment therapy induced complete regression of large established RENCA tumors and raised long-lasting protective immunity. These results have implications for developing clinical antitumoral vaccination regimens in the setting in which tumors express elevated levels of B7-H1 in the presence of abundant Treg cells.

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B7-H1 (Programmed Death-1 Ligand) on Dendritic Cells Is Involved in the Induction and Maintenance of T Cell Anergy

Cited by 246 publications

References 30 publications

Tolerant T cells display impaired trafficking ability

Tolerant T cells display impaired trafficking ability

Expression of B7‐H1 in breast cancer patients is strongly associated with high proliferative Ki‐67‐expressing tumor cells

Targeting Molecular and Cellular Inhibitory Mechanisms for Improvement of Antitumor Memory Responses Reactivated by Tumor Cell Vaccine

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