Abstract
Regulatory T cells (Treg) play important roles in immune system homeostasis, and may also be involved in tumor immunotolerance by suppressing Th1 immune response which is involved in anti-tumor immunity. We have previously reported that immunization with attenuated activated autologous T cells leads to enhanced anti-tumor immunity and upregulated Th1 responses in vivo. However, the underlying molecular mechanisms are not well understood. Here we show that Treg function was significantly downregulated in mice that received immunization of attenuated activated autologous T cells. We found that Foxp3 expression decreased in CD4+CD25+ T cells from the immunized mice. Moreover, CD4+CD25+Foxp3+ Treg obtained from immunized mice exhibited diminished immunosuppression ability compared to those from naïve mice. Further analysis showed that the serum of immunized mice contains a high level of anti-CD25 antibody (about 30 ng/ml, p<0.01 vs controls). Consistent with a role of anti-CD25 response in the downregulation of Treg, adoptive transfer of serum from immunized mice to naïve mice led to a significant decrease in Treg population and function in recipient mice. The triggering of anti-CD25 response in immunized mice can be explained by the fact that CD25 was induced to a high level in the ConA activated autologous T cells used for immunization. Our results demonstrate for the first time that immunization with attenuated activated autologous T cells evokes anti-CD25 antibody production, which leads to impeded CD4+CD25+Foxp3+ Treg expansion and function in vivo. We suggest that dampened Treg function likely contributes to enhanced Th1 response in immunized mice and is at least part of the mechanism underlying the boosted anti-tumor immunity.
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References
Schmitz-Winnenthal FH, Volk C, Z'graggen K, et al. High frequencies of functional tumor-reactive T cells in bone marrow and blood of pancreatic cancer patients. Cancer Res 2005; 65:10079–10087.
Hokey DA, Larregina AT, Erdos G, et al. Tumor cell loaded type-1 polarized dendritic cells induce Th1-mediated tumor immunity. Cancer Res 2005; 65:10059–10067.
Morishima N, Owaki T, Asakawa M, et al. Augmentation of effector CD8+ T cell generation with enhanced granzyme B expression by IL-27. J Immunol 2005; 175:1686–1693.
Kalams SA, Walker BD . The critical need for CD4 help in maintaining effective cytotoxic T lymphocyte responses. J Exp Med 1998; 188:2199–2204.
van Gisbergen KP, Aarnoudse CA, Meijer GA, et al. Dendritic cells recognize tumor-specific glycosylation of carcinoembryonic antigen on colorectal cancer cells through dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin. Cancer Res 2005; 65:5935–5944.
Voigtlander C, Rossner S, Cierpka E, et al. Dendritic cells matured with TNF can be further activated in vitro and after subcutaneous injection in vivo which converts their tolerogenicity into immunogenicity. J Immunother 2006; 29:407–415.
Muthian G, Raikwar HP, Johnson C, et al. COX-2 inhibitors modulate IL-12 signaling through JAK-STAT pathway leading to Th1 response in experimental allergic encephalomyelitis. J Clin Immunol 2006; 26:73–85.
Trinchieri G . Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat Rev Immunol 2003; 3:133–146.
Kumaraguru U, Suvas S, Biswas PS, Azkur AK, Rouse BT . Concomitant helper response rescues otherwise low avidity CD8+ memory CTLs to become efficient effectors in vivo. J Immunol 2004; 172:3719–3724.
Kass R, Agha J, Bellone S, et al. In vitro induction of tumor-specific HLA class I-restricted CD8+ cytotoxic T lymphocytes from patients with locally advanced breast cancer by tumor antigen-pulsed autologous dendritic cells. J Surg Res 2003; 112:189–197.
Xia D, Moyana T, Xiang J . Combinational adenovirus-mediated gene therapy and dendritic cell vaccine in combating well-established tumors. Cell Res 2006; 16:241–259
Finn OJ . Cancer vaccines: between the idea and the reality. Nature Rev Immunol 2003; 3:630–641.
Khong HT, Restifo NP . Natural selection of tumor variants in the generation of 'tumor escape' phenotypes. Nature Immunol 2002; 3:999–1005.
Walker LS, Chodos A, Eggena M, Dooms H, Abbas AK . Antigen-dependent proliferation CD4+CD25+ regulatory T cells in vivo. J Exp Med 2003; 198:249–258.
Yazawa T, Ito T, Kamma H, et al. Complicated mechanisms of class II transactivator transcription deficiency in small cell lung cancer and neuroblastoma. Am J Pathol 2002; 161:291–300.
Yazawa T, Kamma H, Fujiwara M, et al. Lack of class II transactivator causes severe deficiency of HLA-DR expression in small cell lung cancer. J Pathol 1999; 187:191–199.
Francesca Fallarino, Ursula Grohmann, Roberta Bianchi, et al. Th1 and Th2 cell clones to a poorly immunogenic tumor antigen initiate CD8+ T cell-dependent tumor eradication in vivo. J Immunol 2000; 165:5495–5501.
Kalams SA, Walker BD . The critical need for CD4 help in maintaining effective cytotoxic T lymphocyte responses. J Exp Med 1998; 188:2199.
Andersen MH, Ostergaard Pedersen L, Capeller B, et al. Spontaneous cytotoxic T cell responses against surviving-derived MHC class I-restricted T cell epitopes in situ as well as ex vivo in cancer patients. Cancer Res 2001; 61:5964–5971.
Cinatl JJ, Scholz M, Doerr HW . Role of tumor cell immune escape mechanisms in cytomegalovirus-mediated oncomodulation. Med Res Rev 2005; 25:167–185.
Surman D, Dudley ME, Overwijk WW, Restifo NP . Cutting edge: CD4+ T cell control of CD8+ T cell reactivity to a model tumor antigen. J Immunol 2000; 164:562–565.
Weiping Zou . Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nat Rev Cancer 2005; 5:263–274.
Dunn GP, Bruce AT, et al. Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol 2002; 3:991–998.
Maria A Curotto de Lafaille, Juan J Lafaille, et al. CD4+ regulatory T cells in autoimmunity and allergy. Curr Opin Immunol 2002; 14:771–778.
Harald von Boehmer . Mechanisms of suppression by suppressor T cells. Nat Immunol 2005; 6:338–344.
Turk MJ, Guevara-Patino JA, Rizzuto, et al. Concomitant tumor immunity to a poorly immunogenic melanoma is prevented by regulatory T cells. J Exp Med 2004; 200:771–782.
Curiel TJ, Coukos G, Zou L, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 2004; 10:942–949.
Lars A Ormandy, Tina Hillemann, Heiner Wedemeyer, et al. Increased populations of regulatory T cells in peripheral blood of patients with hepatocellular carcinoma. Cancer Res 2005; 65:2457–2464.
Sakaguchi S . Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat Immunol 2005; 6:345–352.
Leach DR, Krummel MF, Allison JP . Enhancement of antitumor immunity by CTLA-4 blockade. Science 1996; 271:1734–1736.
Hurwitz AA, Yu TF, et al. CTLA-4 blockade synergizes with tumor-derived granulocyte macrophage colony-stimulating factor for treatment of an experimental mammary carcinoma. Proc Natl Acad Sci USA 1998; 95:10067–10071.
Shozaburo Onizuka, Isao Tawara, Jun Shimizu, et al. Tumor Rejection by in vivo administration of anti-CD25 (interleukin-2 receptor a) monoclonal antibody. Cancer Res 1999; 59:3128–3133.
Jun Shimizu, Sayuri Yamazaki, Shimon Sakaguchi . Induction of tumor immunity by removing CD25+CD4+ T cells: a common basis between tumor immunity and autoimmunity. J Immunol 1999; 163:5211–5218.
Sutmuller RP, et al. Synergism of cytotoxic T lymphocyte associated antigen 4 blockade and depletion of CD25+ regulatory T cells in antitumor therapy reveals alternative pathways for suppression of autoreactive cytotoxic T lymphocyte responses. J Exp Med 2001; 194:823–832.
Li Wang, Fang Du, Qi Cao, et al. Immunization with autologous T cells enhances in vivo anti-tumor immune responses accompanied by up-regulation of GADD45β. Cell Res 2006; 16:702–712.
Lu LF, Gondek DC, Scott ZA, Noelle RJ . NF kappa B-inducing kinase deficiency results in the development of a subset of regulatory T cells, which shows a hyperproliferative activity upon glucocorticoid-induced TNF receptor family-related gene stimulation. J Immunol 2005; 175:1651–1167.
Wang LX, Chen BG, Plautz GE . Adoptive immunotherapy of advanced tumors with CD62 L-selectin(low) tumor-sensitized T lymphocytes following ex vivo hyperexpansion. J Immunol 2002; 169:3314–3320.
Hannier S, Bitegye C, Demotz S . Early events of TCR signaling are distinct in human Th1 and Th2 cells. J Immunol 2002; 169:1904–1911.
Kim HP, Leonard WJ . The basis for TCR-mediated regulation of the IL-2 receptor alpha chain gene: role of widely separated regulatory elements. EMBO J 2002 21:3051–3059.
von Geldern M, Simm B, Braun M, et al. TCR-independent cytokine stimulation induces non-MHC-restricted T cell activity and is negatively regulated by HLA class I. Eur J Immunol 2006; 36:2347–2358.
Hiura T, Kagamu H, Miura S, et al. Both regulatory T cells and antitumor effector T cells are primed in the same draining lymph nodes during tumor progression. J Immunol 2005; 175:5058–5066.
Peng L, Kjaergaard J, Plautz GE, et al. Helper-independent, L-selectinlow CD8+ T cells with broad anti-tumor efficacy are naturally sensitized during tumor progression. J Immunol 2000; 165:5738–5749.
Enarsson K, Johnsson E, Lindholm C, et al. Differential mechanisms for T lymphocyte recruitment in normal and neoplastic human gastric mucosa. Clin Immunol 2006; 118:24–34.
Matsumura Y, Byrne SN, Nghiem DX, Miyahara Y, Ullrich SE . A role for inflammatory mediators in the induction of immunoregulatory B cells. J Immunol 2006; 177:4810–4817.
Strutt TM, Uzonna J, McKinstry KK, Bretscher PA . Activation of thymic T cells by MHC alloantigen requires syngeneic, activated CD4+ T cells and B cells as APC. Int Immunol 2006; 18:719–728.
Acknowledgements
This work was supported by National Natural Science Foundation of China (No. 30671945), Science and Technology Commission of Shanghai Municipality (Nos. 06JC14044, 05ZR14055, 054319928, 04DZ14902), Shanghai Municipal Education (No. 05BZ26), Shanghai Leading Academic Discipline Project (T0206) and Science Foundation of Shanghai Institute of Immunology (No. 07-A04, to Ningli Li).
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Cao, Q., Wang, L., Du, F. et al. Downregulation of CD4+CD25+ regulatory T cells may underlie enhanced Th1 immunity caused by immunization with activated autologous T cells. Cell Res 17, 627–637 (2007). https://doi.org/10.1038/cr.2007.46
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DOI: https://doi.org/10.1038/cr.2007.46
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