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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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Related in: MedlinePlus

CD70-mediated effects on antigen-specific CD8+ T cell responses require CD27 stimulation during antigen encounter. (A) Wild-type, CD27−/−, CD70 Tg, and CD27−/− × CD70 Tg mice were infected intranasally with influenza virus. At day 9 after infection, spleens were collected, and absolute numbers of NP366-374-specific CD8+ T cells were determined. (B) Reduced CD27 expression on T cells in CD70 Tg × TCR Tg mice requires continuous triggering by CD70. Splenic CD8+ T cells from F5 TCR Tg mice and F5 TCR Tg × CD70 Tg mice were purified and stained with mAbs specific for Vβ11 and CD27 (top). 1 d after adoptive transfer of 4 × 106 purified CD8+ T cells from F5 TCR Tg mice and F5 TCR Tg × CD70 Tg mice into Ly5.1 mice, spleen cells were stained with mAbs specific for CD8, CD27, and Ly5.2 (bottom). Dot plots are gated on CD8+ T cells. (C) Purified CD8+ T cells from F5 TCR Tg mice and F5 TCR Tg × CD70 Tg mice were CFSE-labeled and adoptively transferred into Ly5.1 recipient mice. At 1 d after transfer, mice were infected with influenza virus. 4 d after virus infection, DLN cells were stained with mAbs specific for CD8 and Ly5.2. Flow cytometric histograms of CFSE dilution on CD8 and Ly5.2-positive cells are shown.
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fig3: CD70-mediated effects on antigen-specific CD8+ T cell responses require CD27 stimulation during antigen encounter. (A) Wild-type, CD27−/−, CD70 Tg, and CD27−/− × CD70 Tg mice were infected intranasally with influenza virus. At day 9 after infection, spleens were collected, and absolute numbers of NP366-374-specific CD8+ T cells were determined. (B) Reduced CD27 expression on T cells in CD70 Tg × TCR Tg mice requires continuous triggering by CD70. Splenic CD8+ T cells from F5 TCR Tg mice and F5 TCR Tg × CD70 Tg mice were purified and stained with mAbs specific for Vβ11 and CD27 (top). 1 d after adoptive transfer of 4 × 106 purified CD8+ T cells from F5 TCR Tg mice and F5 TCR Tg × CD70 Tg mice into Ly5.1 mice, spleen cells were stained with mAbs specific for CD8, CD27, and Ly5.2 (bottom). Dot plots are gated on CD8+ T cells. (C) Purified CD8+ T cells from F5 TCR Tg mice and F5 TCR Tg × CD70 Tg mice were CFSE-labeled and adoptively transferred into Ly5.1 recipient mice. At 1 d after transfer, mice were infected with influenza virus. 4 d after virus infection, DLN cells were stained with mAbs specific for CD8 and Ly5.2. Flow cytometric histograms of CFSE dilution on CD8 and Ly5.2-positive cells are shown.

Mentions: To establish whether the CD70-mediated increase in antigen-specific CD8+ T cell responses is dependent on its interaction with CD27, we challenged CD70 Tg mice on a CD27-deficient background with influenza virus. The observed increase in the numbers of splenic influenza-specific CD8+ T cells in CD70 Tg mice was not found in CD27−/− × CD70 Tg mice (Fig. 3 A), indicating an absolute requirement for CD27.


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)

CD70-mediated effects on antigen-specific CD8+ T cell responses require CD27 stimulation during antigen encounter. (A) Wild-type, CD27−/−, CD70 Tg, and CD27−/− × CD70 Tg mice were infected intranasally with influenza virus. At day 9 after infection, spleens were collected, and absolute numbers of NP366-374-specific CD8+ T cells were determined. (B) Reduced CD27 expression on T cells in CD70 Tg × TCR Tg mice requires continuous triggering by CD70. Splenic CD8+ T cells from F5 TCR Tg mice and F5 TCR Tg × CD70 Tg mice were purified and stained with mAbs specific for Vβ11 and CD27 (top). 1 d after adoptive transfer of 4 × 106 purified CD8+ T cells from F5 TCR Tg mice and F5 TCR Tg × CD70 Tg mice into Ly5.1 mice, spleen cells were stained with mAbs specific for CD8, CD27, and Ly5.2 (bottom). Dot plots are gated on CD8+ T cells. (C) Purified CD8+ T cells from F5 TCR Tg mice and F5 TCR Tg × CD70 Tg mice were CFSE-labeled and adoptively transferred into Ly5.1 recipient mice. At 1 d after transfer, mice were infected with influenza virus. 4 d after virus infection, DLN cells were stained with mAbs specific for CD8 and Ly5.2. Flow cytometric histograms of CFSE dilution on CD8 and Ly5.2-positive cells are shown.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2211777&req=5

fig3: CD70-mediated effects on antigen-specific CD8+ T cell responses require CD27 stimulation during antigen encounter. (A) Wild-type, CD27−/−, CD70 Tg, and CD27−/− × CD70 Tg mice were infected intranasally with influenza virus. At day 9 after infection, spleens were collected, and absolute numbers of NP366-374-specific CD8+ T cells were determined. (B) Reduced CD27 expression on T cells in CD70 Tg × TCR Tg mice requires continuous triggering by CD70. Splenic CD8+ T cells from F5 TCR Tg mice and F5 TCR Tg × CD70 Tg mice were purified and stained with mAbs specific for Vβ11 and CD27 (top). 1 d after adoptive transfer of 4 × 106 purified CD8+ T cells from F5 TCR Tg mice and F5 TCR Tg × CD70 Tg mice into Ly5.1 mice, spleen cells were stained with mAbs specific for CD8, CD27, and Ly5.2 (bottom). Dot plots are gated on CD8+ T cells. (C) Purified CD8+ T cells from F5 TCR Tg mice and F5 TCR Tg × CD70 Tg mice were CFSE-labeled and adoptively transferred into Ly5.1 recipient mice. At 1 d after transfer, mice were infected with influenza virus. 4 d after virus infection, DLN cells were stained with mAbs specific for CD8 and Ly5.2. Flow cytometric histograms of CFSE dilution on CD8 and Ly5.2-positive cells are shown.
Mentions: To establish whether the CD70-mediated increase in antigen-specific CD8+ T cell responses is dependent on its interaction with CD27, we challenged CD70 Tg mice on a CD27-deficient background with influenza virus. The observed increase in the numbers of splenic influenza-specific CD8+ T cells in CD70 Tg mice was not found in CD27−/− × CD70 Tg mice (Fig. 3 A), indicating an absolute requirement for CD27.

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