Limits...
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.

Show MeSH

Related in: MedlinePlus

Increased effector CD8+ T cells in NP-specific TCR Tg × CD70 Tg mice. F5 TCR Tg and F5 TCR Tg × CD70 Tg mice were infected intranasally with influenza virus. (A) Frequency of CD43hi-expressing CD8+ T cells in blood at the indicated days after influenza virus infection. Data represent mean values and standard error of five mice per group. Significance of differences was determined by two-tailed Student's t test (*, P < 0.05; **, P < 0.005). (B) Representative FACS® profiles of spleen, lung, and DLNs collected at day 9 after influenza virus infection showing CD43 staining on gated CD8+ T cells of TCR Tg mice (shaded histograms) and TCR Tg × CD70 Tg mice (solid lines). Numbers indicate the percentage of CD43hi cells within the CD8+ T cell compartment. (C) Absolute numbers of CD43hiCD8+ T cells in spleen, lung, and DLNs at day 9 after infection. Data represent mean values and standard error of five mice per group. Significance of differences was determined by two-tailed Student's t test (**, P < 0.005).
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2211777&req=5

fig2: Increased effector CD8+ T cells in NP-specific TCR Tg × CD70 Tg mice. F5 TCR Tg and F5 TCR Tg × CD70 Tg mice were infected intranasally with influenza virus. (A) Frequency of CD43hi-expressing CD8+ T cells in blood at the indicated days after influenza virus infection. Data represent mean values and standard error of five mice per group. Significance of differences was determined by two-tailed Student's t test (*, P < 0.05; **, P < 0.005). (B) Representative FACS® profiles of spleen, lung, and DLNs collected at day 9 after influenza virus infection showing CD43 staining on gated CD8+ T cells of TCR Tg mice (shaded histograms) and TCR Tg × CD70 Tg mice (solid lines). Numbers indicate the percentage of CD43hi cells within the CD8+ T cell compartment. (C) Absolute numbers of CD43hiCD8+ T cells in spleen, lung, and DLNs at day 9 after infection. Data represent mean values and standard error of five mice per group. Significance of differences was determined by two-tailed Student's t test (**, P < 0.005).

Mentions: The aforementioned results indicate that constitutive CD70 expression enhances the expansion of antigen-specific CD8+ T cells upon influenza virus infection. These findings might either be due to a broadening of the T cell repertoire specific for a given influenza antigen or to increased accumulation of the progeny of a similar repertoire of T cells. To determine the effects of constitutive CD70 expression on a monoclonal antigen-specific CD8+ T cell population, we bred mice Tg for the MHC class I–restricted TCR recognizing the influenza virus epitope NP366-374 (F5 TCR Tg; reference 27) with CD70 Tg mice. After influenza infection, F5 TCR Tg × CD70 Tg mice showed increased frequencies of CD8+ T cells with a CD43hi effector phenotype in peripheral blood as compared with F5 TCR Tg mice. This started at day 2 after infection and was maintained until day 31 (Fig. 2 A). At the peak of the response, at approximately day 9 after infection, frequencies as well as absolute numbers of CD43hiCD8+ effector T cells were significantly increased in both spleen and DLNs, but not in lung tissue of F5 TCR Tg × CD70 Tg as compared with F5 TCR Tg mice (Fig. 2, B and C), indicating that CD70 costimulation also enhances expansion of monoclonal CD8+ T cells. This excludes the possibility that our data can be explained by a CD70-mediated, TCR triggering–independent polyclonal T cell activation.


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 effector CD8+ T cells in NP-specific TCR Tg × CD70 Tg mice. F5 TCR Tg and F5 TCR Tg × CD70 Tg mice were infected intranasally with influenza virus. (A) Frequency of CD43hi-expressing CD8+ T cells in blood at the indicated days after influenza virus infection. Data represent mean values and standard error of five mice per group. Significance of differences was determined by two-tailed Student's t test (*, P < 0.05; **, P < 0.005). (B) Representative FACS® profiles of spleen, lung, and DLNs collected at day 9 after influenza virus infection showing CD43 staining on gated CD8+ T cells of TCR Tg mice (shaded histograms) and TCR Tg × CD70 Tg mice (solid lines). Numbers indicate the percentage of CD43hi cells within the CD8+ T cell compartment. (C) Absolute numbers of CD43hiCD8+ T cells in spleen, lung, and DLNs at day 9 after infection. Data represent mean values and standard error of five mice per group. Significance of differences was determined by two-tailed Student's t test (**, P < 0.005).
© Copyright Policy
Related In: Results  -  Collection

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

fig2: Increased effector CD8+ T cells in NP-specific TCR Tg × CD70 Tg mice. F5 TCR Tg and F5 TCR Tg × CD70 Tg mice were infected intranasally with influenza virus. (A) Frequency of CD43hi-expressing CD8+ T cells in blood at the indicated days after influenza virus infection. Data represent mean values and standard error of five mice per group. Significance of differences was determined by two-tailed Student's t test (*, P < 0.05; **, P < 0.005). (B) Representative FACS® profiles of spleen, lung, and DLNs collected at day 9 after influenza virus infection showing CD43 staining on gated CD8+ T cells of TCR Tg mice (shaded histograms) and TCR Tg × CD70 Tg mice (solid lines). Numbers indicate the percentage of CD43hi cells within the CD8+ T cell compartment. (C) Absolute numbers of CD43hiCD8+ T cells in spleen, lung, and DLNs at day 9 after infection. Data represent mean values and standard error of five mice per group. Significance of differences was determined by two-tailed Student's t test (**, P < 0.005).
Mentions: The aforementioned results indicate that constitutive CD70 expression enhances the expansion of antigen-specific CD8+ T cells upon influenza virus infection. These findings might either be due to a broadening of the T cell repertoire specific for a given influenza antigen or to increased accumulation of the progeny of a similar repertoire of T cells. To determine the effects of constitutive CD70 expression on a monoclonal antigen-specific CD8+ T cell population, we bred mice Tg for the MHC class I–restricted TCR recognizing the influenza virus epitope NP366-374 (F5 TCR Tg; reference 27) with CD70 Tg mice. After influenza infection, F5 TCR Tg × CD70 Tg mice showed increased frequencies of CD8+ T cells with a CD43hi effector phenotype in peripheral blood as compared with F5 TCR Tg mice. This started at day 2 after infection and was maintained until day 31 (Fig. 2 A). At the peak of the response, at approximately day 9 after infection, frequencies as well as absolute numbers of CD43hiCD8+ effector T cells were significantly increased in both spleen and DLNs, but not in lung tissue of F5 TCR Tg × CD70 Tg as compared with F5 TCR Tg mice (Fig. 2, B and C), indicating that CD70 costimulation also enhances expansion of monoclonal CD8+ T cells. This excludes the possibility that our data can be explained by a CD70-mediated, TCR triggering–independent polyclonal T cell activation.

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