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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+ and CD25+ cells BALB/c mice were immunized with pChly using the gene gun, and after 35 d, a boost immunization with the same DNA was performed. During boost immunization, mice were treated with purified rat Ig or the mAb indicated. 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 <4,000 IFN-γ+CD8+ T cells/spleen in all samples analyzed (data not depicted). The experiment shown is representative of three similar experiments and represents mean ± SD of three individually analyzed mice per group. Differences to rat Ig treatment: *P < 0.05; **P < 0.01; NS, P > 0.05.
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fig4: Inhibition of memory CD8+ T cell responses by CD4+ and CD25+ cells BALB/c mice were immunized with pChly using the gene gun, and after 35 d, a boost immunization with the same DNA was performed. During boost immunization, mice were treated with purified rat Ig or the mAb indicated. 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 <4,000 IFN-γ+CD8+ T cells/spleen in all samples analyzed (data not depicted). The experiment shown is representative of three similar experiments and represents mean ± SD of three individually analyzed mice per group. Differences to rat Ig treatment: *P < 0.05; **P < 0.01; NS, P > 0.05.

Mentions: Increasing evidence suggests that a subpopulation of CD4+ T cells can suppress immune responses (8, 9). Although a distinct surface phenotype of regulatory T cells has not been defined as yet, these cells are enriched in the CD4+CD25+ T cell population (8, 9). Regulatory T cells are further associated with the expression of CTLA-4/CD152 and TGF-β (13–16). Mice were primed and boosted by DNA immunization, and the role of different cell populations and molecules during the secondary CD8+ T cell response was analyzed by administration of antibodies that either deplete positive cell populations or block the function of the recognized proteins (Fig. 4) . Depletion of CD25+ T cells markedly enhanced the numbers of LLO91–99-tetramer–reactive CD8+ T cells and of CD8+ T cells responding to LLO91–99 stimulation with IFN-γ production, although this increase was less pronounced as compared with that after anti-CD4 mAb treatment. In contrast, mAbs against CD152 or TGF-β did not significantly alter the secondary CD8+ T cell response (Fig. 4).


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+ and CD25+ cells BALB/c mice were immunized with pChly using the gene gun, and after 35 d, a boost immunization with the same DNA was performed. During boost immunization, mice were treated with purified rat Ig or the mAb indicated. 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 <4,000 IFN-γ+CD8+ T cells/spleen in all samples analyzed (data not depicted). The experiment shown is representative of three similar experiments and represents mean ± SD of three individually analyzed mice per group. Differences to rat Ig treatment: *P < 0.05; **P < 0.01; NS, P > 0.05.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2196063&req=5

fig4: Inhibition of memory CD8+ T cell responses by CD4+ and CD25+ cells BALB/c mice were immunized with pChly using the gene gun, and after 35 d, a boost immunization with the same DNA was performed. During boost immunization, mice were treated with purified rat Ig or the mAb indicated. 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 <4,000 IFN-γ+CD8+ T cells/spleen in all samples analyzed (data not depicted). The experiment shown is representative of three similar experiments and represents mean ± SD of three individually analyzed mice per group. Differences to rat Ig treatment: *P < 0.05; **P < 0.01; NS, P > 0.05.
Mentions: Increasing evidence suggests that a subpopulation of CD4+ T cells can suppress immune responses (8, 9). Although a distinct surface phenotype of regulatory T cells has not been defined as yet, these cells are enriched in the CD4+CD25+ T cell population (8, 9). Regulatory T cells are further associated with the expression of CTLA-4/CD152 and TGF-β (13–16). Mice were primed and boosted by DNA immunization, and the role of different cell populations and molecules during the secondary CD8+ T cell response was analyzed by administration of antibodies that either deplete positive cell populations or block the function of the recognized proteins (Fig. 4) . Depletion of CD25+ T cells markedly enhanced the numbers of LLO91–99-tetramer–reactive CD8+ T cells and of CD8+ T cells responding to LLO91–99 stimulation with IFN-γ production, although this increase was less pronounced as compared with that after anti-CD4 mAb treatment. In contrast, mAbs against CD152 or TGF-β did not significantly alter the secondary CD8+ T cell response (Fig. 4).

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