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Regulatory CD4+CD25+ T cells restrict memory CD8+ T cell responses.

Kursar M, Bonhagen K, Fensterle J, Köhler A, Hurwitz R, Kamradt T, Kaufmann SH, Mittrücker HW - J. Exp. Med. (2002)

Bottom Line: In terms of cytokine production and cytotoxicity, the enlarged CD8+ T cell population consisted of functional effector T cells.Our results demonstrate that CD4+ T cells control the CD8+ T cell response in two directions.Initially, they promote the generation of a CD8+ T cell responses and later they restrain the strength of the CD8+ T cell memory response.

View Article: PubMed Central - PubMed

Affiliation: Max Planck Institute for Infection Biology, Department of Immunology. Deutsches Rheumaforschungszentrum, Schumannstr. 21/22, 10117 Berlin, Germany.

ABSTRACT
CD4+ T cell help is important for the generation of CD8+ T cell responses. We used depleting anti-CD4 mAb to analyze the role of CD4+ T cells for memory CD8+ T cell responses after secondary infection of mice with the intracellular bacterium Listeria monocytogenes, or after boost immunization by specific peptide or DNA vaccination. Surprisingly, anti-CD4 mAb treatment during secondary CD8+ T cell responses markedly enlarged the population size of antigen-specific CD8+ T cells. After boost immunization with peptide or DNA, this effect was particularly profound, and antigen-specific CD8+ T cell populations were enlarged at least 10-fold. In terms of cytokine production and cytotoxicity, the enlarged CD8+ T cell population consisted of functional effector T cells. In depletion and transfer experiments, the suppressive function could be ascribed to CD4+CD25+ T cells. Our results demonstrate that CD4+ T cells control the CD8+ T cell response in two directions. Initially, they promote the generation of a CD8+ T cell responses and later they restrain the strength of the CD8+ T cell memory response. Down-modulation of CD8+ T cell responses during infection could prevent harmful consequences after eradication of the pathogen.

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LLO91–99–specific CD8+ T cell response during primary and secondary infection with L. monocytogenes (A) Primary infection: mice infected with L. monocytogenes were left untreated (control) or received anti-CD4 mAb (anti-CD4). (B) Secondary infection: mice were infected and after 60 d challenged with L. monocytogenes. During challenge infection, mice were left untreated or received anti-CD4 mAb. At the indicated days, spleen cells were stained with Cy5-conjugated anti-CD8α mAb, FITC-conjugated anti-CD62L mAb, and PE-labeled LLO91–99-tetramers, and analyzed by flow cytometry after the addition of propidium iodide. Figures show percent values of live CD62Llowtetramer+ cells of total CD8+ cells. Data represent mean ± SD of three mice per group and time point. Experiments in A and B are representative of two or three experiments, respectively.
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fig1: LLO91–99–specific CD8+ T cell response during primary and secondary infection with L. monocytogenes (A) Primary infection: mice infected with L. monocytogenes were left untreated (control) or received anti-CD4 mAb (anti-CD4). (B) Secondary infection: mice were infected and after 60 d challenged with L. monocytogenes. During challenge infection, mice were left untreated or received anti-CD4 mAb. At the indicated days, spleen cells were stained with Cy5-conjugated anti-CD8α mAb, FITC-conjugated anti-CD62L mAb, and PE-labeled LLO91–99-tetramers, and analyzed by flow cytometry after the addition of propidium iodide. Figures show percent values of live CD62Llowtetramer+ cells of total CD8+ cells. Data represent mean ± SD of three mice per group and time point. Experiments in A and B are representative of two or three experiments, respectively.

Mentions: Infection of mice with L. monocytogenes causes a strong CD8+ T cell response that is crucial for protective immunity. There is also a strong induction of a CD4+ T cell response during L. monocytogenes infection, but the relevance of these cells during infection is less clear (2, 3). An important function of CD4+ T cells is to provide help for the generation of CD8+ T cell responses. To analyze this function in more detail, BALB/c mice were treated with a depleting anti-CD4 mAb and infected with L. monocytogenes. The CD8+ T cell response was analyzed with MHC class I tetramers containing the immunodominant CD8+ T cell epitope LLO91–99 (4, 10). During primary infection, depletion of CD4+ T cells caused an ∼50% reduction of the frequency of LLO91–99–specific CD8+ T cells in spleens of infected mice (Fig. 1 A). Surprisingly, depletion of CD4+ T cells during secondary infection did not diminish, but increased frequencies and numbers of listeria-specific CD8+ T cells (Fig. 1 B, and unpublished data). During both primary and secondary infection, neither the bacterial titers in spleen and liver nor the course of bacterial clearance were significantly altered by anti-CD4 mAb treatment (unpublished data).


Regulatory CD4+CD25+ T cells restrict memory CD8+ T cell responses.

Kursar M, Bonhagen K, Fensterle J, Köhler A, Hurwitz R, Kamradt T, Kaufmann SH, Mittrücker HW - J. Exp. Med. (2002)

LLO91–99–specific CD8+ T cell response during primary and secondary infection with L. monocytogenes (A) Primary infection: mice infected with L. monocytogenes were left untreated (control) or received anti-CD4 mAb (anti-CD4). (B) Secondary infection: mice were infected and after 60 d challenged with L. monocytogenes. During challenge infection, mice were left untreated or received anti-CD4 mAb. At the indicated days, spleen cells were stained with Cy5-conjugated anti-CD8α mAb, FITC-conjugated anti-CD62L mAb, and PE-labeled LLO91–99-tetramers, and analyzed by flow cytometry after the addition of propidium iodide. Figures show percent values of live CD62Llowtetramer+ cells of total CD8+ cells. Data represent mean ± SD of three mice per group and time point. Experiments in A and B are representative of two or three experiments, respectively.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2196063&req=5

fig1: LLO91–99–specific CD8+ T cell response during primary and secondary infection with L. monocytogenes (A) Primary infection: mice infected with L. monocytogenes were left untreated (control) or received anti-CD4 mAb (anti-CD4). (B) Secondary infection: mice were infected and after 60 d challenged with L. monocytogenes. During challenge infection, mice were left untreated or received anti-CD4 mAb. At the indicated days, spleen cells were stained with Cy5-conjugated anti-CD8α mAb, FITC-conjugated anti-CD62L mAb, and PE-labeled LLO91–99-tetramers, and analyzed by flow cytometry after the addition of propidium iodide. Figures show percent values of live CD62Llowtetramer+ cells of total CD8+ cells. Data represent mean ± SD of three mice per group and time point. Experiments in A and B are representative of two or three experiments, respectively.
Mentions: Infection of mice with L. monocytogenes causes a strong CD8+ T cell response that is crucial for protective immunity. There is also a strong induction of a CD4+ T cell response during L. monocytogenes infection, but the relevance of these cells during infection is less clear (2, 3). An important function of CD4+ T cells is to provide help for the generation of CD8+ T cell responses. To analyze this function in more detail, BALB/c mice were treated with a depleting anti-CD4 mAb and infected with L. monocytogenes. The CD8+ T cell response was analyzed with MHC class I tetramers containing the immunodominant CD8+ T cell epitope LLO91–99 (4, 10). During primary infection, depletion of CD4+ T cells caused an ∼50% reduction of the frequency of LLO91–99–specific CD8+ T cells in spleens of infected mice (Fig. 1 A). Surprisingly, depletion of CD4+ T cells during secondary infection did not diminish, but increased frequencies and numbers of listeria-specific CD8+ T cells (Fig. 1 B, and unpublished data). During both primary and secondary infection, neither the bacterial titers in spleen and liver nor the course of bacterial clearance were significantly altered by anti-CD4 mAb treatment (unpublished data).

Bottom Line: In terms of cytokine production and cytotoxicity, the enlarged CD8+ T cell population consisted of functional effector T cells.Our results demonstrate that CD4+ T cells control the CD8+ T cell response in two directions.Initially, they promote the generation of a CD8+ T cell responses and later they restrain the strength of the CD8+ T cell memory response.

View Article: PubMed Central - PubMed

Affiliation: Max Planck Institute for Infection Biology, Department of Immunology. Deutsches Rheumaforschungszentrum, Schumannstr. 21/22, 10117 Berlin, Germany.

ABSTRACT
CD4+ T cell help is important for the generation of CD8+ T cell responses. We used depleting anti-CD4 mAb to analyze the role of CD4+ T cells for memory CD8+ T cell responses after secondary infection of mice with the intracellular bacterium Listeria monocytogenes, or after boost immunization by specific peptide or DNA vaccination. Surprisingly, anti-CD4 mAb treatment during secondary CD8+ T cell responses markedly enlarged the population size of antigen-specific CD8+ T cells. After boost immunization with peptide or DNA, this effect was particularly profound, and antigen-specific CD8+ T cell populations were enlarged at least 10-fold. In terms of cytokine production and cytotoxicity, the enlarged CD8+ T cell population consisted of functional effector T cells. In depletion and transfer experiments, the suppressive function could be ascribed to CD4+CD25+ T cells. Our results demonstrate that CD4+ T cells control the CD8+ T cell response in two directions. Initially, they promote the generation of a CD8+ T cell responses and later they restrain the strength of the CD8+ T cell memory response. Down-modulation of CD8+ T cell responses during infection could prevent harmful consequences after eradication of the pathogen.

Show MeSH
Related in: MedlinePlus