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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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Increased generation of NP-specific CD8+ T cells in CD70 Tg mice after EL4-NP tumor challenge. (A) Wild-type and CD70 Tg mice were challenged subcutaneously with 106 EL4-NP tumor cells, and tumor size was measured at the indicated days after tumor challenge. Data represent mean values and standard error of six mice per group. (B) Frequency of NP366-374-specific CD8+ T cells in blood of wild-type and CD70 Tg mice. Significance of differences was determined by two-tailed Student's t test (*, P < 0.05). (C) Absolute numbers of NP366-374-specific CD8+ cells in spleen and DLNs at day 13 after tumor challenge. Significance of differences was determined by two-tailed Student's t test (*, P < 0.05).
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fig4: Increased generation of NP-specific CD8+ T cells in CD70 Tg mice after EL4-NP tumor challenge. (A) Wild-type and CD70 Tg mice were challenged subcutaneously with 106 EL4-NP tumor cells, and tumor size was measured at the indicated days after tumor challenge. Data represent mean values and standard error of six mice per group. (B) Frequency of NP366-374-specific CD8+ T cells in blood of wild-type and CD70 Tg mice. Significance of differences was determined by two-tailed Student's t test (*, P < 0.05). (C) Absolute numbers of NP366-374-specific CD8+ cells in spleen and DLNs at day 13 after tumor challenge. Significance of differences was determined by two-tailed Student's t test (*, P < 0.05).

Mentions: The effects of CD27 ligation in vivo on antitumor CD8+ T cell responses were analyzed using EL4 tumor cells that express the influenza A virus–derived NP366-374 epitope. These tumor cells induce an NP366-374-specific CD8+ T cell response and tumor rejection in normal mice (33). Subcutaneously inoculated EL4-NP tumor cells were rejected in wild-type and CD70 Tg mice with similar kinetics (Fig. 4 A). The percentage of NP366-374-specific CD8+ T cells at the peak of the response (day 13 after tumor challenge) and on consecutive days, was increased approximately two- to threefold in the blood of CD70 Tg mice (Fig. 4 B). Similarly, the absolute number of NP366-374-specific CD8+ T cells was significantly increased in the spleen of CD70 Tg mice and slightly increased in DLNs (Fig. 4 C). As in influenza infection, increased percentages of CD43hiCD8+ T cells were observed in the peripheral lymphoid organs of CD70 Tg mice (unpublished data). It is unlikely that the B cell depletion occurring in CD70 Tg mice (25) is involved in the observed effects on CD8+ T cell responses because B cell–deficient mice show similar CD8+ T cell responses after EL4-NP challenge (unpublished data). Together, these data show that CD27 stimulation augments the expansion and maintenance of the antigen-specific T cell pool after tumor challenge.


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)

Increased generation of NP-specific CD8+ T cells in CD70 Tg mice after EL4-NP tumor challenge. (A) Wild-type and CD70 Tg mice were challenged subcutaneously with 106 EL4-NP tumor cells, and tumor size was measured at the indicated days after tumor challenge. Data represent mean values and standard error of six mice per group. (B) Frequency of NP366-374-specific CD8+ T cells in blood of wild-type and CD70 Tg mice. Significance of differences was determined by two-tailed Student's t test (*, P < 0.05). (C) Absolute numbers of NP366-374-specific CD8+ cells in spleen and DLNs at day 13 after tumor challenge. Significance of differences was determined by two-tailed Student's t test (*, P < 0.05).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2211777&req=5

fig4: Increased generation of NP-specific CD8+ T cells in CD70 Tg mice after EL4-NP tumor challenge. (A) Wild-type and CD70 Tg mice were challenged subcutaneously with 106 EL4-NP tumor cells, and tumor size was measured at the indicated days after tumor challenge. Data represent mean values and standard error of six mice per group. (B) Frequency of NP366-374-specific CD8+ T cells in blood of wild-type and CD70 Tg mice. Significance of differences was determined by two-tailed Student's t test (*, P < 0.05). (C) Absolute numbers of NP366-374-specific CD8+ cells in spleen and DLNs at day 13 after tumor challenge. Significance of differences was determined by two-tailed Student's t test (*, P < 0.05).
Mentions: The effects of CD27 ligation in vivo on antitumor CD8+ T cell responses were analyzed using EL4 tumor cells that express the influenza A virus–derived NP366-374 epitope. These tumor cells induce an NP366-374-specific CD8+ T cell response and tumor rejection in normal mice (33). Subcutaneously inoculated EL4-NP tumor cells were rejected in wild-type and CD70 Tg mice with similar kinetics (Fig. 4 A). The percentage of NP366-374-specific CD8+ T cells at the peak of the response (day 13 after tumor challenge) and on consecutive days, was increased approximately two- to threefold in the blood of CD70 Tg mice (Fig. 4 B). Similarly, the absolute number of NP366-374-specific CD8+ T cells was significantly increased in the spleen of CD70 Tg mice and slightly increased in DLNs (Fig. 4 C). As in influenza infection, increased percentages of CD43hiCD8+ T cells were observed in the peripheral lymphoid organs of CD70 Tg mice (unpublished data). It is unlikely that the B cell depletion occurring in CD70 Tg mice (25) is involved in the observed effects on CD8+ T cell responses because B cell–deficient mice show similar CD8+ T cell responses after EL4-NP challenge (unpublished data). Together, these data show that CD27 stimulation augments the expansion and maintenance of the antigen-specific T cell pool after tumor challenge.

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