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Tumor rejection induced by CD70-mediated quantitative and qualitative effects on effector CD8+ T cell formation.

Arens R, Schepers K, Nolte MA, van Oosterwijk MF, van Lier RA, Schumacher TN, van Oers MH - J. Exp. Med. (2004)

Bottom Line: However, it is unclear to what extent CD8+ T cell instruction in vivo is modulated by costimulatory signals.Concomitantly, the quality of antigen-specific T cells improved as evidenced by increased interferon (IFN)-gamma production and a greater cytotoxic potential on a per cell basis.Thus, CD70 costimulation enhances both the expansion and per cell activity of antigen-specific CD8+ T cells.

View Article: PubMed Central - PubMed

Affiliation: Laboratory for Experimental Immunology, Academic Medical Center, University of Amsterdam, Netherlands.

ABSTRACT
In vivo priming of antigen-specific CD8+ T cells results in their expansion and differentiation into effector T cells followed by contraction into a memory T cell population that can be maintained for life. Recent evidence suggests that after initial antigenic stimulation, the magnitude and kinetics of the CD8+ T cell response are programmed. However, it is unclear to what extent CD8+ T cell instruction in vivo is modulated by costimulatory signals. Here, we demonstrate that constitutive ligation of the tumor necrosis factor receptor family member CD27 by its ligand CD70 quantitatively augments CD8+ T cell responses to influenza virus infection and EL-4 tumor challenge in vivo by incrementing initial expansion and maintaining higher numbers of antigen-specific T cells in the memory phase. Concomitantly, the quality of antigen-specific T cells improved as evidenced by increased interferon (IFN)-gamma production and a greater cytotoxic potential on a per cell basis. As an apparent consequence, the superior effector T cell formation induced by CD70 protected against a lethal dose of poorly immunogenic EL4 tumor cells in a CD8+ T cell- and IFN-gamma-dependent manner. Thus, CD70 costimulation enhances both the expansion and per cell activity of antigen-specific CD8+ T cells.

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CD8+ T cell– and IFN-γ–dependent tumor rejection in CD70 Tg mice. Mice were challenged subcutaneously with 106 EL4 or EL4-GFP tumor cells. Tumors were measured, and mice were killed when tumors reached diameters of >15 mm. (A) EL4 and (B) EL4-GFP tumor rejection in CD70 Tg mice. Tumor size of wild-type and CD70 Tg mice was measured at the indicated days after tumor challenge. Data represent mean values and standard error of eight mice per group. (C) Increased frequencies of CD8+ T cells and tumor specific-CD8+ T cells in spleen and tumors after EL4-GFP challenge as determined using anti-CD8 mAbs and H-2Db-GagL85-93 tetramers at day 9 after tumor challenge. (D) CD8+ T cell infiltrates (red) in EL4-GFP tumors (blue) from wild-type and CD70 Tg mice at day 9 after tumor challenge as determined by immunohistochemistry. (E) CD8+ T cells are critically involved in EL4 tumor rejection in CD70 Tg mice. Tumor size was measured at the indicated days after EL4 tumor challenge in mice treated with either anti-CD4 or anti-CD8 mAbs. Data represent mean values and standard error from five mice per group. (F) IFN-γ is critically involved in EL4 tumor rejection in CD70 Tg mice. Tumor size of IFN-γ−/− and IFN-γ−/− × CD70 Tg mice was measured at the indicated days after tumor challenge. Data represent mean and standard error from five mice per group.
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fig6: CD8+ T cell– and IFN-γ–dependent tumor rejection in CD70 Tg mice. Mice were challenged subcutaneously with 106 EL4 or EL4-GFP tumor cells. Tumors were measured, and mice were killed when tumors reached diameters of >15 mm. (A) EL4 and (B) EL4-GFP tumor rejection in CD70 Tg mice. Tumor size of wild-type and CD70 Tg mice was measured at the indicated days after tumor challenge. Data represent mean values and standard error of eight mice per group. (C) Increased frequencies of CD8+ T cells and tumor specific-CD8+ T cells in spleen and tumors after EL4-GFP challenge as determined using anti-CD8 mAbs and H-2Db-GagL85-93 tetramers at day 9 after tumor challenge. (D) CD8+ T cell infiltrates (red) in EL4-GFP tumors (blue) from wild-type and CD70 Tg mice at day 9 after tumor challenge as determined by immunohistochemistry. (E) CD8+ T cells are critically involved in EL4 tumor rejection in CD70 Tg mice. Tumor size was measured at the indicated days after EL4 tumor challenge in mice treated with either anti-CD4 or anti-CD8 mAbs. Data represent mean values and standard error from five mice per group. (F) IFN-γ is critically involved in EL4 tumor rejection in CD70 Tg mice. Tumor size of IFN-γ−/− and IFN-γ−/− × CD70 Tg mice was measured at the indicated days after tumor challenge. Data represent mean and standard error from five mice per group.

Mentions: The aforementioned findings showed that in the presence of a strong CD27 signal, both quantity and quality of CD8+ T cell responses improve. To evaluate the possible benefits of this for increased immunity, the ability of CD8+ T cells to control growth of poorly immunogenic tumors was evaluated in CD70 Tg and wild-type mice. In view of this purpose, we examined the response to EL4 tumor cells and EL4 tumor cells transduced with a retroviral vector containing GFP and the Moloney-derived MHC class I–restricted GagL85-93 epitope. The GagL epitope encoded by the Moloney retrovirus is derived from an alternative translation initiation site, and presentation of this epitope is insufficient to allow immune control of EL4-GFP tumors in wild-type mice (33). EL4 and EL4-GFP tumor cells grew progressively in wild-type mice, whereas in CD70 Tg mice, both EL4 and EL4-GFP tumors regressed at day 9 after tumor inoculation (Fig. 6, A and B). At day 9 after tumor challenge, spleens and tumors of CD70 Tg mice challenged with EL4-GFP contained increased percentages of tumor-specific CD8+ T cells as compared with wild-type mice challenged with EL4-GFP (Fig. 6 C). Furthermore, immunohistochemistry of tumor tissue at day 9 after tumor challenge showed that in CD70 Tg mice, the tumors contained larger infiltrates of CD8+ T cells (Fig. 6 D).


Tumor rejection induced by CD70-mediated quantitative and qualitative effects on effector CD8+ T cell formation.

Arens R, Schepers K, Nolte MA, van Oosterwijk MF, van Lier RA, Schumacher TN, van Oers MH - J. Exp. Med. (2004)

CD8+ T cell– and IFN-γ–dependent tumor rejection in CD70 Tg mice. Mice were challenged subcutaneously with 106 EL4 or EL4-GFP tumor cells. Tumors were measured, and mice were killed when tumors reached diameters of >15 mm. (A) EL4 and (B) EL4-GFP tumor rejection in CD70 Tg mice. Tumor size of wild-type and CD70 Tg mice was measured at the indicated days after tumor challenge. Data represent mean values and standard error of eight mice per group. (C) Increased frequencies of CD8+ T cells and tumor specific-CD8+ T cells in spleen and tumors after EL4-GFP challenge as determined using anti-CD8 mAbs and H-2Db-GagL85-93 tetramers at day 9 after tumor challenge. (D) CD8+ T cell infiltrates (red) in EL4-GFP tumors (blue) from wild-type and CD70 Tg mice at day 9 after tumor challenge as determined by immunohistochemistry. (E) CD8+ T cells are critically involved in EL4 tumor rejection in CD70 Tg mice. Tumor size was measured at the indicated days after EL4 tumor challenge in mice treated with either anti-CD4 or anti-CD8 mAbs. Data represent mean values and standard error from five mice per group. (F) IFN-γ is critically involved in EL4 tumor rejection in CD70 Tg mice. Tumor size of IFN-γ−/− and IFN-γ−/− × CD70 Tg mice was measured at the indicated days after tumor challenge. Data represent mean and standard error from five mice per group.
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Related In: Results  -  Collection

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fig6: CD8+ T cell– and IFN-γ–dependent tumor rejection in CD70 Tg mice. Mice were challenged subcutaneously with 106 EL4 or EL4-GFP tumor cells. Tumors were measured, and mice were killed when tumors reached diameters of >15 mm. (A) EL4 and (B) EL4-GFP tumor rejection in CD70 Tg mice. Tumor size of wild-type and CD70 Tg mice was measured at the indicated days after tumor challenge. Data represent mean values and standard error of eight mice per group. (C) Increased frequencies of CD8+ T cells and tumor specific-CD8+ T cells in spleen and tumors after EL4-GFP challenge as determined using anti-CD8 mAbs and H-2Db-GagL85-93 tetramers at day 9 after tumor challenge. (D) CD8+ T cell infiltrates (red) in EL4-GFP tumors (blue) from wild-type and CD70 Tg mice at day 9 after tumor challenge as determined by immunohistochemistry. (E) CD8+ T cells are critically involved in EL4 tumor rejection in CD70 Tg mice. Tumor size was measured at the indicated days after EL4 tumor challenge in mice treated with either anti-CD4 or anti-CD8 mAbs. Data represent mean values and standard error from five mice per group. (F) IFN-γ is critically involved in EL4 tumor rejection in CD70 Tg mice. Tumor size of IFN-γ−/− and IFN-γ−/− × CD70 Tg mice was measured at the indicated days after tumor challenge. Data represent mean and standard error from five mice per group.
Mentions: The aforementioned findings showed that in the presence of a strong CD27 signal, both quantity and quality of CD8+ T cell responses improve. To evaluate the possible benefits of this for increased immunity, the ability of CD8+ T cells to control growth of poorly immunogenic tumors was evaluated in CD70 Tg and wild-type mice. In view of this purpose, we examined the response to EL4 tumor cells and EL4 tumor cells transduced with a retroviral vector containing GFP and the Moloney-derived MHC class I–restricted GagL85-93 epitope. The GagL epitope encoded by the Moloney retrovirus is derived from an alternative translation initiation site, and presentation of this epitope is insufficient to allow immune control of EL4-GFP tumors in wild-type mice (33). EL4 and EL4-GFP tumor cells grew progressively in wild-type mice, whereas in CD70 Tg mice, both EL4 and EL4-GFP tumors regressed at day 9 after tumor inoculation (Fig. 6, A and B). At day 9 after tumor challenge, spleens and tumors of CD70 Tg mice challenged with EL4-GFP contained increased percentages of tumor-specific CD8+ T cells as compared with wild-type mice challenged with EL4-GFP (Fig. 6 C). Furthermore, immunohistochemistry of tumor tissue at day 9 after tumor challenge showed that in CD70 Tg mice, the tumors contained larger infiltrates of CD8+ T cells (Fig. 6 D).

Bottom Line: However, it is unclear to what extent CD8+ T cell instruction in vivo is modulated by costimulatory signals.Concomitantly, the quality of antigen-specific T cells improved as evidenced by increased interferon (IFN)-gamma production and a greater cytotoxic potential on a per cell basis.Thus, CD70 costimulation enhances both the expansion and per cell activity of antigen-specific CD8+ T cells.

View Article: PubMed Central - PubMed

Affiliation: Laboratory for Experimental Immunology, Academic Medical Center, University of Amsterdam, Netherlands.

ABSTRACT
In vivo priming of antigen-specific CD8+ T cells results in their expansion and differentiation into effector T cells followed by contraction into a memory T cell population that can be maintained for life. Recent evidence suggests that after initial antigenic stimulation, the magnitude and kinetics of the CD8+ T cell response are programmed. However, it is unclear to what extent CD8+ T cell instruction in vivo is modulated by costimulatory signals. Here, we demonstrate that constitutive ligation of the tumor necrosis factor receptor family member CD27 by its ligand CD70 quantitatively augments CD8+ T cell responses to influenza virus infection and EL-4 tumor challenge in vivo by incrementing initial expansion and maintaining higher numbers of antigen-specific T cells in the memory phase. Concomitantly, the quality of antigen-specific T cells improved as evidenced by increased interferon (IFN)-gamma production and a greater cytotoxic potential on a per cell basis. As an apparent consequence, the superior effector T cell formation induced by CD70 protected against a lethal dose of poorly immunogenic EL4 tumor cells in a CD8+ T cell- and IFN-gamma-dependent manner. Thus, CD70 costimulation enhances both the expansion and per cell activity of antigen-specific CD8+ T cells.

Show MeSH
Related in: MedlinePlus