Regulatory CD4+CD25+ T cells restrict memory CD8+ T cell responses - PubMed (original) (raw)
Regulatory CD4+CD25+ T cells restrict memory CD8+ T cell responses
Mischo Kursar et al. J Exp Med. 2002.
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.
Figures
Figure 1.
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.
Figure 2.
Response against peptide and DNA boost-immunization of _L. monocytogenes_–primed mice after CD4+ T cell depletion. Mice were infected with L. monocytogenes. After 100 d, mice were immunized either with the peptide LLO91–99 in incomplete Freund's adjuvant subcutaneously or with pChly DNA using the gene gun. Groups of mice were left untreated (control) or were injected with anti-CD4 mAb during the boost immunization. On day 7, spleen cells were stained and analyzed by flow cytometry. Dot plots depict CD62L and LLO91–99-tetramer staining of viable CD8α gated cells. The experiment shown is representative of two independent experiments with three individually analyzed mice per group.
Figure 3.
Effector functions of LLO91–99–specific CD8+ T cells after prime/boost DNA immunization. Mice were immunized with pChly using the gene gun. After 50 d, a boost immunization with the same DNA was performed. Mice were left untreated (control) or were treated with anti-CD4 mAb during the boost immunization. At day 7, mice were killed. (A) Spleen cells were stained and analyzed by flow cytometry. Dot plots depict CD62L and LLO91–99-tetramer staining of viable CD8-gated T cells and figures represent percent values calculated for CD8+ T cells only. (B) Spleen cells were cultured for 5 h with or without the peptide LLO91–99 and stained extracellularly for CD8 and intracellularly for IFN-γ and TNF-α or with isotype control mAbs. Dot blots show CD8-gated cells, and figures give percent values calculated for CD8+ T cells only. Values for isotype controls were below 0.05% (data not depicted). Dot blots in A and B show corresponding results from the same mice. (C) Spleen cells from untreated (diamonds) or anti-CD4 mAb-treated mice (triangles) were incubated for 4 h with target cells with (filled symbols) or without LLO91–99 (open symbols). After 4 h, lysis of target cells was determined. C shows results from three individually analyzed mice per group. Experiments in A–C are representative for at least two independent experiments with three individually analyzed mice per experimental group in each experiment.
Figure 4.
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.
Figure 5.
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.
Similar articles
- Depletion of CD4+ T cells during immunization with nonviable Listeria monocytogenes causes enhanced CD8+ T cell-mediated protection against listeriosis.
Kursar M, Köhler A, Kaufmann SH, Mittrücker HW. Kursar M, et al. J Immunol. 2004 Mar 1;172(5):3167-72. doi: 10.4049/jimmunol.172.5.3167. J Immunol. 2004. PMID: 14978123 - CD40 signaling converts a minimally immunogenic antigen into a potent vaccine against the intracellular pathogen Listeria monocytogenes.
Rolph MS, Kaufmann SH. Rolph MS, et al. J Immunol. 2001 Apr 15;166(8):5115-21. doi: 10.4049/jimmunol.166.8.5115. J Immunol. 2001. PMID: 11290793 - A specific role for B cells in the generation of CD8 T cell memory by recombinant Listeria monocytogenes.
Shen H, Whitmire JK, Fan X, Shedlock DJ, Kaech SM, Ahmed R. Shen H, et al. J Immunol. 2003 Feb 1;170(3):1443-51. doi: 10.4049/jimmunol.170.3.1443. J Immunol. 2003. PMID: 12538706 - Listeria monocytogenes: a model pathogen to study antigen-specific memory CD8 T cell responses.
Khan SH, Badovinac VP. Khan SH, et al. Semin Immunopathol. 2015 May;37(3):301-10. doi: 10.1007/s00281-015-0477-5. Epub 2015 Apr 10. Semin Immunopathol. 2015. PMID: 25860798 Free PMC article. Review. - Probing CD8 T cell responses with Listeria monocytogenes infection.
Condotta SA, Richer MJ, Badovinac VP, Harty JT. Condotta SA, et al. Adv Immunol. 2012;113:51-80. doi: 10.1016/B978-0-12-394590-7.00005-1. Adv Immunol. 2012. PMID: 22244579 Review.
Cited by
- CD39 expression by regulatory T cells participates in CD8+ T cell suppression during experimental Trypanosoma cruzi infection.
Araujo Furlan CL, Boccardo S, Rodriguez C, Mary VS, Gimenez CMS, Robson SC, Gruppi A, Montes CL, Acosta Rodríguez EV. Araujo Furlan CL, et al. PLoS Pathog. 2024 Apr 29;20(4):e1012191. doi: 10.1371/journal.ppat.1012191. eCollection 2024 Apr. PLoS Pathog. 2024. PMID: 38683845 Free PMC article. - AIM™ platform: A new immunotherapy approach for viral diseases.
Langan D, Wang R, Tidwell K, Mitiku S, Farrell A, Johnson C, Parks A, Suarez L, Jain S, Kim S, Jones K, Oelke M, Zeldis J. Langan D, et al. Front Med (Lausanne). 2022 Dec 23;9:1070529. doi: 10.3389/fmed.2022.1070529. eCollection 2022. Front Med (Lausanne). 2022. PMID: 36619639 Free PMC article. - Implications of regulatory T cells in anti-cancer immunity: from pathogenesis to therapeutics.
Dwivedi M, Tiwari S, Kemp EH, Begum R. Dwivedi M, et al. Heliyon. 2022 Aug 27;8(8):e10450. doi: 10.1016/j.heliyon.2022.e10450. eCollection 2022 Aug. Heliyon. 2022. PMID: 36082331 Free PMC article. Review. - Pityriasis rosea, pityriasis rosea-like eruptions, and herpes zoster in the setting of COVID-19 and COVID-19 vaccination.
Drago F, Broccolo F, Ciccarese G. Drago F, et al. Clin Dermatol. 2022 Sep-Oct;40(5):586-590. doi: 10.1016/j.clindermatol.2022.01.002. Epub 2022 Jan 31. Clin Dermatol. 2022. PMID: 35093476 Free PMC article. - Crosstalk of Microorganisms and Immune Responses in Autoimmune Neuroinflammation: A Focus on Regulatory T Cells.
Schroeter CB, Huntemann N, Bock S, Nelke C, Kremer D, Pfeffer K, Meuth SG, Ruck T. Schroeter CB, et al. Front Immunol. 2021 Oct 7;12:747143. doi: 10.3389/fimmu.2021.747143. eCollection 2021. Front Immunol. 2021. PMID: 34691057 Free PMC article. Review.
References
- Kaufmann, S.H.E. 1993. Immunity to intracellular bacteria. Annu. Rev. Immunol. 11:129–163. - PubMed
- Mittrücker, H.-W., A. Köhler, and S.H.E. Kaufmann. 2000. Substantial in vivo proliferation of CD4+ and CD8+ T lymphocytes during secondary Listeria monocytogenes infection. Eur. J. Immunol. 30:1053–1059. - PubMed
- Ladel, C.H., I.E. Flesch, J. Arnoldi, and S.H.E. Kaufmann. 1994. Studies with MHC-deficient knock-out mice reveal impact of both MHC I- and MHC II-dependent T cell responses on Listeria monocytogenes infection. J. Immunol. 153:3116–3122. - PubMed
- Busch, D.H., I.M. Pilip, S. Vijh, and E.G. Pamer. 1998. Coordinate regulation of complex T cell populations responding to bacterial infections. Immunity. 8:353–362. - PubMed
- Geginat, G., S. Schenk, M. Skoberne, W. Göbel, and H. Hof. 2001. A novel approach of direct ex vivo epitope mapping identifies dominant and subdominant CD4 and CD8 T cell epitopes from Listeria monocytogenes. J. Immunol. 166:1877–1884. - PubMed
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Research Materials