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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 antigen-specific CD8+ T cells in CD70 Tg mice after influenza virus infection. Wild-type and CD70 Tg mice were infected intranasally with influenza virus. (A) Representative FACS® profiles of blood cells collected at day 0 and at day 9 after infection showing H-2Db-NP366-374 tetramer staining versus CD8. Numbers indicate the percentages of H-2Db-NP366-374–specific cells within the CD8+ T cell compartment. No cells were stained with Moloney virus–specific (H-2Db-GagL85-93) tetramers (not depicted). (B) Frequency of H2-Db-NP366-374 tetramer positive cells among CD8+ T cells in blood at the indicated days after influenza virus infection. Data represent mean values and standard error from 10 mice per group. Significance of differences was determined by two-tailed Student's t test (*, P < 0.05; **, P < 0.005). (C) Expansion and contraction of NP366-374-specific CD8+ T cells in blood was normalized to the peak of the response (at day 9). (D) Absolute numbers of NP366-374-specific and (E) PA224-233-specific CD8+ T cells in spleens, DLNs, and lungs 9 d after infection. Data representing the mean and standard error from six mice per group are shown. Significance of differences was determined by two-tailed Student's t test (*, P < 0.05; **, P < 0.005). Both groups of mice showed no difference in kinetics of viral clearance. (F) Contraction of antigen-specific CD8+ T cells in the spleen was normalized to the peak of the response (at day 9).
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fig1: Increased generation of antigen-specific CD8+ T cells in CD70 Tg mice after influenza virus infection. Wild-type and CD70 Tg mice were infected intranasally with influenza virus. (A) Representative FACS® profiles of blood cells collected at day 0 and at day 9 after infection showing H-2Db-NP366-374 tetramer staining versus CD8. Numbers indicate the percentages of H-2Db-NP366-374–specific cells within the CD8+ T cell compartment. No cells were stained with Moloney virus–specific (H-2Db-GagL85-93) tetramers (not depicted). (B) Frequency of H2-Db-NP366-374 tetramer positive cells among CD8+ T cells in blood at the indicated days after influenza virus infection. Data represent mean values and standard error from 10 mice per group. Significance of differences was determined by two-tailed Student's t test (*, P < 0.05; **, P < 0.005). (C) Expansion and contraction of NP366-374-specific CD8+ T cells in blood was normalized to the peak of the response (at day 9). (D) Absolute numbers of NP366-374-specific and (E) PA224-233-specific CD8+ T cells in spleens, DLNs, and lungs 9 d after infection. Data representing the mean and standard error from six mice per group are shown. Significance of differences was determined by two-tailed Student's t test (*, P < 0.05; **, P < 0.005). Both groups of mice showed no difference in kinetics of viral clearance. (F) Contraction of antigen-specific CD8+ T cells in the spleen was normalized to the peak of the response (at day 9).

Mentions: To test the impact of CD27 ligation on the kinetics of the immune reaction in a physiological virus infection model, influenza virus-specific CD8+ T cell responses of intranasally influenza virus–infected wild-type and CD70 Tg mice were compared longitudinally using MHC class I tetramers. At the peak of the response, at day 9 after infection, influenza-specific CD8+ T cell frequencies as measured by NP366-374 tetramer staining in peripheral blood were moderately increased in CD70 Tg mice as compared with wild-type mice (Fig. 1, A and B). Analyses of the ensuing time points revealed a modest delay in contraction of the influenza-specific CD8+ T cell pool in peripheral blood of CD70 Tg mice (Fig. 1, B and C). Finally, percentages of tetramer-binding T cells remaining long after viral clearance (day 27) were significantly higher in the CD70 Tg mice than in wild-type mice (Fig. 1 B). The kinetics and magnitude of the influenza-specific CD8+ T cells paralleled the expression of the effector cell marker 1B11 (35), recognizing the activation-associated glycoform of CD43 on the total CD8+ T cell population (unpublished data).


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 antigen-specific CD8+ T cells in CD70 Tg mice after influenza virus infection. Wild-type and CD70 Tg mice were infected intranasally with influenza virus. (A) Representative FACS® profiles of blood cells collected at day 0 and at day 9 after infection showing H-2Db-NP366-374 tetramer staining versus CD8. Numbers indicate the percentages of H-2Db-NP366-374–specific cells within the CD8+ T cell compartment. No cells were stained with Moloney virus–specific (H-2Db-GagL85-93) tetramers (not depicted). (B) Frequency of H2-Db-NP366-374 tetramer positive cells among CD8+ T cells in blood at the indicated days after influenza virus infection. Data represent mean values and standard error from 10 mice per group. Significance of differences was determined by two-tailed Student's t test (*, P < 0.05; **, P < 0.005). (C) Expansion and contraction of NP366-374-specific CD8+ T cells in blood was normalized to the peak of the response (at day 9). (D) Absolute numbers of NP366-374-specific and (E) PA224-233-specific CD8+ T cells in spleens, DLNs, and lungs 9 d after infection. Data representing the mean and standard error from six mice per group are shown. Significance of differences was determined by two-tailed Student's t test (*, P < 0.05; **, P < 0.005). Both groups of mice showed no difference in kinetics of viral clearance. (F) Contraction of antigen-specific CD8+ T cells in the spleen was normalized to the peak of the response (at day 9).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2211777&req=5

fig1: Increased generation of antigen-specific CD8+ T cells in CD70 Tg mice after influenza virus infection. Wild-type and CD70 Tg mice were infected intranasally with influenza virus. (A) Representative FACS® profiles of blood cells collected at day 0 and at day 9 after infection showing H-2Db-NP366-374 tetramer staining versus CD8. Numbers indicate the percentages of H-2Db-NP366-374–specific cells within the CD8+ T cell compartment. No cells were stained with Moloney virus–specific (H-2Db-GagL85-93) tetramers (not depicted). (B) Frequency of H2-Db-NP366-374 tetramer positive cells among CD8+ T cells in blood at the indicated days after influenza virus infection. Data represent mean values and standard error from 10 mice per group. Significance of differences was determined by two-tailed Student's t test (*, P < 0.05; **, P < 0.005). (C) Expansion and contraction of NP366-374-specific CD8+ T cells in blood was normalized to the peak of the response (at day 9). (D) Absolute numbers of NP366-374-specific and (E) PA224-233-specific CD8+ T cells in spleens, DLNs, and lungs 9 d after infection. Data representing the mean and standard error from six mice per group are shown. Significance of differences was determined by two-tailed Student's t test (*, P < 0.05; **, P < 0.005). Both groups of mice showed no difference in kinetics of viral clearance. (F) Contraction of antigen-specific CD8+ T cells in the spleen was normalized to the peak of the response (at day 9).
Mentions: To test the impact of CD27 ligation on the kinetics of the immune reaction in a physiological virus infection model, influenza virus-specific CD8+ T cell responses of intranasally influenza virus–infected wild-type and CD70 Tg mice were compared longitudinally using MHC class I tetramers. At the peak of the response, at day 9 after infection, influenza-specific CD8+ T cell frequencies as measured by NP366-374 tetramer staining in peripheral blood were moderately increased in CD70 Tg mice as compared with wild-type mice (Fig. 1, A and B). Analyses of the ensuing time points revealed a modest delay in contraction of the influenza-specific CD8+ T cell pool in peripheral blood of CD70 Tg mice (Fig. 1, B and C). Finally, percentages of tetramer-binding T cells remaining long after viral clearance (day 27) were significantly higher in the CD70 Tg mice than in wild-type mice (Fig. 1 B). The kinetics and magnitude of the influenza-specific CD8+ T cells paralleled the expression of the effector cell marker 1B11 (35), recognizing the activation-associated glycoform of CD43 on the total CD8+ T cell population (unpublished data).

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