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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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Inhibition of memory CD8+ T cell responses by CD4+CD25+ cells in a transfer model SCID mice received CD4-depleted cells from mice previously immunized by DNA vaccination. Groups of mice received in addition purified CD4+CD25− and CD4+CD25+ cells from either naive or L. monocytogenes–infected mice. Immediately after cell transfer, mice were DNA immunized with pChly. On day 7, spleen cells were analyzed with LLO91–99-tetramers (A) and for IFN-γ production after incubation with LLO91–99 (B), as described in Fig. 3. Without peptide stimulation we observed <1,500 IFN-γ+CD8+ T cells/spleen in all samples analyzed (data not depicted). The experiment shown represents mean ± SD of three individually analyzed mice per group and is representative for three independent experiments. Differences to gene gun treated mice that received only CD4+ T cell–depleted cells: *P < 0.05; **P < 0.01; NS, P > 0.05.
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fig5: Inhibition of memory CD8+ T cell responses by CD4+CD25+ cells in a transfer model SCID mice received CD4-depleted cells from mice previously immunized by DNA vaccination. Groups of mice received in addition purified CD4+CD25− and CD4+CD25+ cells from either naive or L. monocytogenes–infected mice. Immediately after cell transfer, mice were DNA immunized with pChly. On day 7, spleen cells were analyzed with LLO91–99-tetramers (A) and for IFN-γ production after incubation with LLO91–99 (B), as described in Fig. 3. Without peptide stimulation we observed <1,500 IFN-γ+CD8+ T cells/spleen in all samples analyzed (data not depicted). The experiment shown represents mean ± SD of three individually analyzed mice per group and is representative for three independent experiments. Differences to gene gun treated mice that received only CD4+ T cell–depleted cells: *P < 0.05; **P < 0.01; NS, P > 0.05.

Mentions: So far, our assumption that CD4+CD25+ T cells suppress CD8+ memory T cell responses is based on antibody depletion experiments. However, antibody treatment, particularly anti-CD4 mAb treatment, could have effects beyond CD4+ T cell depletion, which we cannot fully exclude. Therefore, we assessed the role of CD4+CD25+ T cells for memory CD8+ T cell responses in SCID mice that were immunized after reconstitution with defined T cell populations. SCID mice received CD4-depleted cells from mice that had been DNA immunized 5 wk earlier. Groups of these mice received purified CD25+ T cells (>90% CD4+) or purified CD4+CD25− T cells in addition. Purified T cells were derived either from naive mice, or from mice that had been infected with L. monocytogenes 3 mo before transfer. After reconstitution, SCID mice were DNA immunized. 7 d later, LLO91–99-tetramer–reactive T cells and IFN-γ production after LLO91–99 stimulation were determined (Fig. 5) . In SCID mice reconstituted with CD4-depleted cells from previously immunized mice, DNA immunization caused strong proliferation of LLO91–99–specific CD8+ T cells. Addition of CD4+CD25− T cells from either naive or L. monocytogenes infected mice did not significantly alter expansion of these CD8+ T cell populations. In contrast, cotransfer of CD4+CD25+ T cells markedly impaired the LLO91–99–specific CD8+ T cell response, and this inhibition was observed with CD4+CD25+ T cells derived from both naive and L. monocytogenes–infected mice.


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)

Inhibition of memory CD8+ T cell responses by CD4+CD25+ cells in a transfer model SCID mice received CD4-depleted cells from mice previously immunized by DNA vaccination. Groups of mice received in addition purified CD4+CD25− and CD4+CD25+ cells from either naive or L. monocytogenes–infected mice. Immediately after cell transfer, mice were DNA immunized with pChly. On day 7, spleen cells were analyzed with LLO91–99-tetramers (A) and for IFN-γ production after incubation with LLO91–99 (B), as described in Fig. 3. Without peptide stimulation we observed <1,500 IFN-γ+CD8+ T cells/spleen in all samples analyzed (data not depicted). The experiment shown represents mean ± SD of three individually analyzed mice per group and is representative for three independent experiments. Differences to gene gun treated mice that received only CD4+ T cell–depleted cells: *P < 0.05; **P < 0.01; NS, P > 0.05.
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Related In: Results  -  Collection

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fig5: Inhibition of memory CD8+ T cell responses by CD4+CD25+ cells in a transfer model SCID mice received CD4-depleted cells from mice previously immunized by DNA vaccination. Groups of mice received in addition purified CD4+CD25− and CD4+CD25+ cells from either naive or L. monocytogenes–infected mice. Immediately after cell transfer, mice were DNA immunized with pChly. On day 7, spleen cells were analyzed with LLO91–99-tetramers (A) and for IFN-γ production after incubation with LLO91–99 (B), as described in Fig. 3. Without peptide stimulation we observed <1,500 IFN-γ+CD8+ T cells/spleen in all samples analyzed (data not depicted). The experiment shown represents mean ± SD of three individually analyzed mice per group and is representative for three independent experiments. Differences to gene gun treated mice that received only CD4+ T cell–depleted cells: *P < 0.05; **P < 0.01; NS, P > 0.05.
Mentions: So far, our assumption that CD4+CD25+ T cells suppress CD8+ memory T cell responses is based on antibody depletion experiments. However, antibody treatment, particularly anti-CD4 mAb treatment, could have effects beyond CD4+ T cell depletion, which we cannot fully exclude. Therefore, we assessed the role of CD4+CD25+ T cells for memory CD8+ T cell responses in SCID mice that were immunized after reconstitution with defined T cell populations. SCID mice received CD4-depleted cells from mice that had been DNA immunized 5 wk earlier. Groups of these mice received purified CD25+ T cells (>90% CD4+) or purified CD4+CD25− T cells in addition. Purified T cells were derived either from naive mice, or from mice that had been infected with L. monocytogenes 3 mo before transfer. After reconstitution, SCID mice were DNA immunized. 7 d later, LLO91–99-tetramer–reactive T cells and IFN-γ production after LLO91–99 stimulation were determined (Fig. 5) . In SCID mice reconstituted with CD4-depleted cells from previously immunized mice, DNA immunization caused strong proliferation of LLO91–99–specific CD8+ T cells. Addition of CD4+CD25− T cells from either naive or L. monocytogenes infected mice did not significantly alter expansion of these CD8+ T cell populations. In contrast, cotransfer of CD4+CD25+ T cells markedly impaired the LLO91–99–specific CD8+ T cell response, and this inhibition was observed with CD4+CD25+ T cells derived from both naive and L. monocytogenes–infected mice.

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