About this Journal Submit a Manuscript Table of Contents
ISRN Immunology
Volume 2011 (2011), Article ID 497397, 6 pages
http://dx.doi.org/10.5402/2011/497397
Review Article

The Roles of CD4+ T Cells in Tumor Immunity

1Department of Internal Medicine, National Taiwan University Hospital, Taipei 100, Taiwan
2Institute of Anatomy and Cell Biology, School of Medicine, National Yang-Ming University, Taipei 122, Taiwan
3Department of Medical Research, National Taiwan University Hospital, Taipei 100, Taiwan

Received 8 August 2011; Accepted 20 September 2011

Academic Editors: B. Favier and B. Sawitzki

Copyright © 2011 Yo-Ping Lai et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Activation of CD8+ cytotoxic T cells has long been regarded as a major antitumor mechanism of the immune system. Emerging evidence suggests that CD4+ T cells are required for the generation and maintenance of effective CD8+ cytotoxic and memory T cells, a phenomenon known as CD4+ T-cell help. CD4+ T-cell help facilitates the optimal expansion, trafficking, and effector function of CD8+ T cells, thereby enhancing tumor destruction. In addition, a specialized subset of CD4+ T cells, CD4+CD25+ regulatory T cells (TRegs), effectively hampers anti-tumor immune responses, which has been proposed to be one of the major tumor immune evasion mechanisms. Here, we review recent advances in deciphering how anti-tumor immune responses are orchestrated by CD4+ T cells. We will also discuss the immunotherapeutic potential of CD4+ T-cell manipulation in anti-tumor immune response.

1. Introduction

Cell-mediated immunity plays an important role in immune responses against cancer. For example, CD8+ cytotoxic T lymphocytes (CTLs) are key effector cells in antitumor immunity [1]. In hosts with tumors, however, tumor-specific CD8+ T-cell responses are usually weak. The key to this paradoxical observation may lie in the fact that CD4+ T-cell help is insufficient for driving an effective antitumor immunity. CD4+ T cells play a cardinal role in orchestrating antibody production and the activation and expansion of CD8+ T cells, a phenomenon known as CD4+ T-cell help [2, 3]. CD4+ T-cell help is also required for the generation and maintenance of CD8+ T-cell memory [49]. Of note, such CD4+ T-cell help that programs the CD8+ T-cell responses is favored at the time of CD8+ T-cell priming [7, 912]. Importantly, increasing evidence has shown that CD4+ T cells significantly contribute to tumor protection in vivo [1316].

Tumor cells, on the other hand, have also evolved different mechanisms to escape from host immunity, thereby defeating conventional cancer immunotherapy. Typical immunity-escaping strategies employed by tumor cells include the downregulation of target antigens and antigen-presenting machinery, as well as the recruitment of a specialized subset of CD4+ T cells, CD4+CD25+ regulatory T cells (TRegs), into tumors [1719]. In fact, the activation of TRegs has been proposed to be one of the major tumor immune escape mechanisms [2024]. This paper summarizes current understanding of the role of CD4+ T cells in shaping and augmenting antitumor immunity. We also discuss the adverse role of TRegs in tumor immune surveillance.

2. The Conventional Concept of CD4+ T-Cell Help

Several in vitro and in vivo studies of allogeneic reactions support the idea that CD4+ T-cell help is required for the optimal induction and clonal expansion of cytotoxic CD8+ T-cell responses [3, 14, 2529]. Several recent studies further suggest that CD4+ T cells can directly interact with CD8+ T cells via CD40–CD154 interactions [30], which directly contrasts with the early notion that CD4+ and CD8+ T cells are brought together on the same antigen-presenting cell for the effective delivery of interleukin-2 (IL-2) to neighboring CD8+ T cells [3, 31]. Alternatively, CD4+ T cells may condition dendritic cells to increase their ability to stimulate CD8+ T cells [3235]. Moreover, a full CD8+ T-cell response is critically elicited by a temporal release of IL-2 from CD4+ T cells [36], which is consistent with the findings that neutralization of IL-2 significantly limits CD8+ T-cell growth [3740]. Furthermore, IL-2 has previously been shown to be crucial for maintaining CD8+ T-cell function in vivo [41, 42].

CD4+ T cells also play a pivotal role in the generation and maintenance of functional and long-lived CD8+ memory T cells [49]. Of note, the presence of the CD4+ T-cell help during the priming phase of CD8+ T-cell activation is essential for the differentiation of CD8+ effector cells into memory cells [5, 7, 9, 11, 12]. By contrast, in the absence of CD4+ T-cell help during priming, less CD8+ T cells can develop into memory cells, and there is an increased likelihood of finding memory cells with phenotypic and functional defects [43]. These events are likewise required for eliciting an effective tumor-specific immunity.

3. CD4+ T Cells Orchestrate the Antitumor Immunity

3.1. Priming or Postpriming

During the priming phase CD8+ T cells, activated CD4+ T cells may help the activation of CD8+ CTL that occurs within tumor-draining lymph nodes. As discussed above, CD4+ T cells play important roles in facilitating the initial activation and expansion of CD8+ T cells. CD4+ T cells orchestrate the antitumor CD8+ CTL responses through direct cell-cell interaction and IL-2 stimulation. CD4+ T cells may directly help CD8+ T-cell activation via CD40–CD154 interaction [30, 44, 45]. Alternatively, activated CD4+ T cells may also produce IL-2 to support the activation and proliferation of CD8+ T cells [3740]. Furthermore, CD4+ T cells also “license” dendritic cells (DCs) to activate CD8+ T cells either by cross-presenting tumor antigens to CD8+ T cells or by inducing the production and expression of cytokines and costimulatory molecules, respectively [3235, 46]. The preceding events, altogether known as CD4+ T-cell help, significantly augment antitumor CD8+ T-cell responses during the priming phase.

CD4+ T cells may also provide help during the postpriming phase that occurs at the tumor site. An optimal CD4+ T-cell response can augment the accumulation of CD8+ T cells within tumor and promote the expansion, trafficking, and differentiation of the tumor-specific CD8+ T cells, both of which enhance antitumor immunity [13, 4751]. Although nontumor-specific CD4+ T cells can instigate significant expansion of tumor-specific CD8+ T cells, they fail to promote the accumulation of the cells within tumor. In contrast, provision of tumor-specific CD4+ T-cell help increases the CD8+ T-cell expansion and augments the accumulation of both CD4+ and CD8+ T cells within tumor, leading to greater tumor destruction [52]. Moreover, cognate CD4+ memory T cells enhance the expansion of cognate CD8+ memory T cells as well as the infiltration and accumulation of these cells within tumor [53]. Taken together, the number of tumor-infiltrating CD4+ T cells correlates with the antitumor efficacy of CD8+ T-cell responses, suggesting that the tumor-specific CD4+ T cells render the tumor environment receptive for CD8+ T-cell residence or facilitate the access of CD8+ T cells to tumor.

3.2. CD4+ T Cells Program the Tumor-Specific CD8+ T Cells

It becomes apparent that the great number of tumor-reactive CTL mounted by vaccination or provided by adoptive immunotherapy does not always attain effective tumor regression [5457]. One of the most important factors that account for the poor antitumor responses is the lack of CD4+ T-cell help.

CD4+ T cells play an important role in the development of effective antitumor immunity [1316, 58]. Both the number and function of tumor-specific CTL are significantly enhanced in the presence of tumor-specific CD4+ T-cell responses, whereas depletion of CD4+ T cells facilitates tumor progression and abrogates the survival of tumor-bearing hosts, indicating the importance of tumor-specific CD4+ T-cell help in maintaining the tumor-reactive CTL function in vivo [13, 14]. In addition, the efficacy of the antitumor responses induced by the combined administration of human CD4+ and CD8+ T cells is notably better than that by applying CD4+ or CD8+ T cells alone [59]. Interestingly, adaptively transferred CD4+ T cells can also activate endogenous CD8+ effector cells to induce CTL responses. Therefore, CD4+ T-cell help is critical for promoting effective antitumor CTL responses, which is achieved not only by maintaining the numbers of tumor-specific CD8+ T cells but also by the optimal CTL function.

The induction of an optimal primary T-cell immune response requires two signals [60, 61]. The first signal is elicited by the engagement of TCR by the peptide/MHC complex, which determines the specificity of T-cell activation [62]. The second signal, the costimulatory signal, is provided by ligation of accessory molecules, such as CD28 on T cells, to lower the activation threshold of TCRs, which further ensures the tumor-reactive cytolytic activity of CD8+ T cells [63, 64]. However, it has become clear that several other signals are also required to determine whether effective CD8+ memory T cells will be generated and maintained. For example, CD4+ T-cell help during the priming phase can program CD8+ T-cell response and shapes the long-term fate and function of CD8+ memory T cells [57, 12]. In contrast, in host deficient of CD4+ T cells, CD8+ memory T cells show few in numbers and the secondary CD8+ T-cell response is compromised. With CD4+ T-cell help during early priming, the CD4+ T-cell-derived IL-2 signals can drive the differentiation of CD8+ T cells to produce greater quantities of IFN-γ and Granzyme B on encountering tumor in vivo [36]. Accordingly, the tumor-specific CD8+ T cells may exert long-term antitumor activity when they are stimulated as well as helped by CD4+ T cells during priming. However, most tumor cells do not express the MHC class II molecules required for the successful generation of tumor-reactive CD4+ T cells. In addition, tumor cells may secrete some immunosuppressive mediators and induce a state of anergy [65, 66]. Altogether, the unhelped tumor-specific CD8+ T cells ultimately develop functional deficits. This impairment leads to the suboptimal tumor-specific CD8+ memory T-cell response and tumor progression.

3.3. The Unconventional Effects of CD4+ T-Cell Help on Tumor Control

In addition to providing help for tumor-reactive CD8+ T-cell responses, CD4+ T cells may mediate tumor rejection through other mechanisms, including (1) cytotoxic effect on tumor cells, (2) upregulation of MHC molecules expression, (3) inhibition of angiogenesis, and (4) induction of tumor dormancy.

CD8+ T cells are specialized for lytic function and most of the solid tumors express MHC class I, but not class II molecules. Therefore, it is believed that CD8+ T cells are the main effector cells responsible for destroying tumors. However, tumor-reactive CD4+ T cells can develop cytotoxic activity and mediate tumor rejection via MHC-class-II-restricted antigen recognition in tumor cells [67, 68], suggesting that CD4+ T cells per se may be the effector cell of antitumor responses. Induction of tumor-reactive CD4+ T cells exhibiting cytolytic activities may therefore offer an advantage for cancer immunotherapy in cancer patients. The antitumor effects of CD4+ T cells are dependent on cytokine signaling, especially IFN-γ and TNF-α. These two cytokines, produced by CD4+ T cells, have cytotoxic effect on tumor cells [6971]. IFN-γ can up-regulate MHC molecules to increase the number of pMHC complexes as well as to alter the antigen-processing machinery [72]. Consequently, the tumor recognition is enhanced, resulting in greater tumor cell lysis. In addition, CD4+ T cells induce tumor dormancy that prevents tumor escape [73]. This tumor-growth-inhibiting effect strictly requires both IFN-γ and TNF-α signaling. In this scenario, the absence of IFN-γ or TNF-α could lead to tumor progression and transformation. Furthermore, CD4+ T cells inhibit tumor angiogenesis through a combined action of IFN-γ and TNF-α, which induces DCs to produce potent antiangiogenic chemokines, CXCL10 and CXCL9 [70, 74]. Together, these studies highlight the antitumor mechanisms underlying how CD4+ T cells act in a tumor setting.

3.4. Regulatory T Cells

TRegs, a specialized subset of CD4+ T cells, can suppress immune responses and maintain T-cell tolerance to self-antigens [75, 76]. It is known that TRegs hamper the functions of CD8+ T cells and natural killer cells, the key effector cells of antitumor immunity [77, 78]. Accordingly, TRegs-mediated immunosuppression has been proposed to be one of the important mechanisms involved in the tumor immune evasion.

An accumulation of TRegs in tumors can dampen T-cell immunity to tumors and is thus the main obstacle to successful immunotherapy and active vaccination [7981]. The frequency of TRegs present in peripheral blood of patients with various cancers is higher than that of normal population [7983]. Notably, TRegs isolated from peripheral blood, ascites, or solid tumors remain suppressive to T-cell activation in vitro [79]. Likewise, TRegs from tumor-bearing mice inhibited tumor rejection [2123], indicating that TRegs suppress tumor-specific immunity and limit antitumor resistance. In contrast, depletion of TRegs with anti-CD25 monoclonal antibody in animal models enhance antitumor immunity and tumor regression, further suggesting the involvement of TRegs in tumor growth [19, 8486]. Furthermore, when tumor-specific CD8+ T cells were adoptively transferred with either TRegs or CD4+CD25 T cells into host with melanoma, CD8+ T-cell-mediated immunity was abolished in those receiving TReg cells but not CD4+CD25 T cells [79, 87, 88]. Collectively, these studies provide strong evidence that TReg cells can attenuate the antitumor immunity by downregulating the antitumor immune responses and ultimately facilitate the development of cancer.

Based on the fact that TRegs can suppress tumor-specific immunity, well-planned manipulations of TRegs, including depletion, blocking trafficking into tumors, and reducing their differentiation and suppressive mechanisms, may sensitize the established tumors to be destroyed by tumor-specific immune responses and thus provide additional therapeutic opportunities. It will be beneficial to tumor eradication by combining this strategy with various current therapeutic approaches.

4. Conclusion

Our present understanding of the importance of CD4+ T cells for antitumor immunity can be stressed in several facets. Firstly, an early notion is that CD4+ T cells provide help for inducing and sustaining the tumor-specific CD8+ T-cell responses. Secondly, the CD4+ T-cell help at priming is required for the generation and maintenance of CD8+ memory T cells. Thirdly, CD4+ T cells mediate the tumor rejection through cytotoxic effects on tumor cells, the upregulation of MHC molecules expression, antiangiogenesis, and the induction of tumor dormancy. Fourthly, the existence of the specialized subset of CD4+ T cells TRegs indeed compromises antitumor immune responses. These insights pave the way for incorporating a holistic approach to improve cancer vaccination. Finally, future attempts to enhance an effective tumor-reactive immune response by immunotherapy or vaccination should be made by promoting tumor-specific CD4+ T-cell responses and targeting suppressive molecules on TRegs.

Acknowledgment

This work was supported by National Science Council Grant 99-2314-B-002-081-MY3 (to S.-C. Chen).

References

  1. H. Tanaka, H. Yoshizawa, Y. Yamaguchi et al., “Successful adoptive immunotherapy of murine poorly immunogenic tumor with specific effector cells generated from gene-modified tumor-primed lymph node cells,” Journal of Immunology, vol. 162, no. 6, pp. 3574–3582, 1999. View at Scopus
  2. N. A. Mitchison, “The carrier effect in the secondary response to hapten-protein conjugates. II. Cellular cooperation,” European Journal of Immunology, vol. 1, no. 1, pp. 18–27, 1971. View at Scopus
  3. J. A. Keene and J. Forman, “Helper activity is required for the in vivo generation of cytotoxic T lymphocytes,” Journal of Experimental Medicine, vol. 155, no. 3, pp. 768–782, 1982. View at Scopus
  4. E. M. Janssen, N. M. Droin, E. E. Lemmens et al., “CD4+ T-cell help controls CD8+ T-cell memory via TRAIL-mediated activation-induced cell death,” Nature, vol. 434, no. 7029, pp. 88–93, 2005. View at Publisher · View at Google Scholar · View at Scopus
  5. J. C. Sun and M. J. Bevan, “Defective CD8 T cell memory following acute infection without CD4 T cell help,” Science, vol. 300, no. 5617, pp. 339–342, 2003. View at Publisher · View at Google Scholar · View at Scopus
  6. C. Bourgeois and C. Tanchot, “CD4 T cells are required for CD8 T cell memory generation,” European Journal of Immunology, vol. 33, no. 12, pp. 3225–3231, 2003. View at Publisher · View at Google Scholar · View at Scopus
  7. D. J. Shedlock and H. Shen, “Requirement for CD4 T cell help in generating functional CD8 T cell memory,” Science, vol. 300, no. 5617, pp. 337–339, 2003. View at Publisher · View at Google Scholar · View at Scopus
  8. E. M. Janssen, E. E. Lemmens, T. Wolfe, U. Christen, M. G. Von Herrath, and S. P. Schoenberger, “CD4+ T cells are required for secondary expansion and memory in CD8+ T lymphocytes,” Nature, vol. 421, no. 6925, pp. 852–856, 2003. View at Publisher · View at Google Scholar · View at Scopus
  9. D. Masopust, S. M. Kaech, E. J. Wherry, and R. Ahmed, “The role of programming in memory T-cell development,” Current Opinion in Immunology, vol. 16, no. 2, pp. 217–225, 2004. View at Publisher · View at Google Scholar · View at Scopus
  10. Y. X. Sun, J. Wang, C. E. Shelburne et al., “Expression of CXCR4 and CXCL12 (SDF-1) in human prostate cancers (PCa) in vivo,” Journal of Cellular Biochemistry, vol. 89, no. 3, pp. 462–473, 2003. View at Publisher · View at Google Scholar · View at Scopus
  11. J. C. Sun, M. A. Williams, and M. J. Bevan, “CD4+ T cells are required for the maintenance, not programming, of memory CD8+ T cells after acute infection,” Nature Immunology, vol. 5, no. 9, pp. 927–933, 2004. View at Publisher · View at Google Scholar · View at Scopus
  12. M. A. Williams, A. J. Tyznik, and M. J. Bevan, “Interleukin-2 signals during priming are required for secondary expansion of CD8+ memory T cells,” Nature, vol. 441, no. 7095, pp. 890–893, 2006. View at Publisher · View at Google Scholar · View at Scopus
  13. A. L. Marzo, B. F. Kinnear, R. A. Lake et al., “Tumor-specific CD4+ T cells have a major 'post-licensing' role in CTL mediated anti-tumor immunity,” Journal of Immunology, vol. 165, no. 11, pp. 6047–6055, 2000. View at Scopus
  14. F. Ossendorp, E. Mengedé, M. Camps, R. Filius, and C. J. M. Melief, “Specific T helper cell requirement for optimal induction of cytotoxic T lymphocytes against major histocompatibility complex class II negative tumors,” Journal of Experimental Medicine, vol. 187, no. 5, pp. 693–702, 1998. View at Publisher · View at Google Scholar · View at Scopus
  15. K. Hung, R. Hayashi, A. Lafond-Walker, C. Lowenstein, D. Pardoll, and H. Levitsky, “The central role of CD4+ T cells in the antitumor immune response,” Journal of Experimental Medicine, vol. 188, no. 12, pp. 2357–2368, 1998. View at Publisher · View at Google Scholar · View at Scopus
  16. D. M. Pardoll and S. L. Topalian, “The role of CD4+ T cell responses in antitumor immunity,” Current Opinion in Immunology, vol. 10, no. 5, pp. 588–594, 1998. View at Publisher · View at Google Scholar · View at Scopus
  17. F. Garrido, T. Cabrera, A. Concha, S. Glew, F. Ruiz-Cabello, and P. L. Stern, “Natural history of HLA expression during tumour development,” Immunology Today, vol. 14, no. 10, pp. 491–499, 1993. View at Publisher · View at Google Scholar · View at Scopus
  18. K. E. Hellstrom, I. Hellstrom, and L. Chen, “Can go-stimulated tumor immunity be therapeutically efficacious?” Immunological Reviews, no. 145, pp. 123–145, 1995. View at Scopus
  19. J. Steitz, J. Brück, J. Lenz, J. Knop, and T. Tüting, “Depletion of CD25+CD4+ T cells and treatment with tyrosinase-related protein 2-transduced dendritic cells enhance the interferon α-induced, CD8+ T-cell-dependent immune defense of B16 melanoma,” Cancer Research, vol. 61, no. 24, pp. 8643–8646, 2001.
  20. W. Zou, “Regulatory T cells, tumour immunity and immunotherapy,” Nature Reviews Immunology, vol. 6, no. 4, pp. 295–307, 2006. View at Publisher · View at Google Scholar · View at Scopus
  21. M. J. Berendt and R. J. North, “T-cell-mediated suppression of anti-tumor immunity. An explanation for progressive growth of an immunogenic tumor,” Journal of Experimental Medicine, vol. 151, no. 1, pp. 69–80, 1980. View at Scopus
  22. I. Bursuker and R. J. North, “Generation and decay of the immune response to a progressive fibrosarcoma. II. Failure to demonstrate postexcision immunity after the onset of T cell-mediated suppression of immunity,” Journal of Experimental Medicine, vol. 159, no. 5, pp. 1312–1321, 1984. View at Scopus
  23. R. J. North and I. Bursuker, “Generation and decay of the immune response to a progressive fibrosarcoma. I. Ly-1+2- suppressor T cells down-regulate the generation of Ly-1-2+ effector T cells,” Journal of Experimental Medicine, vol. 159, no. 5, pp. 1295–1311, 1984. View at Scopus
  24. S. Fujimoto, M. Greene, and A. H. Sehon, “Immunosuppressor T cells in tumor bearing hosts,” Immunological Communications, vol. 4, no. 3, pp. 201–217, 1975. View at Scopus
  25. M. J. Bevan, “Immunology: stimulating killer cells,” Nature, vol. 342, no. 6249, pp. 478–479, 1989. View at Publisher · View at Google Scholar · View at Scopus
  26. S. Guerder and P. Matzinger, “Activation versus tolerance: a decision made by T helper cells,” Cold Spring Harbor Symposia on Quantitative Biology, vol. 54, no. 2, pp. 799–805, 1989. View at Scopus
  27. F. H. Bach, C. Grillot-Courvalin, and O. J. Kuperman, “Antigenic requirements for triggering of cytotoxic T lymphocytes,” Immunological Reviews, vol. 35, pp. 76–96, 1977. View at Scopus
  28. S. R. M. Bennett, F. R. Carbone, F. Karamalis, J. F. A. P. Miller, and W. R. Heath, “Induction of a CD8+ cytotoxic T lymphocyte response by cross-priming requires cognate CD4+ T cell help,” Journal of Experimental Medicine, vol. 186, no. 1, pp. 65–70, 1997. View at Publisher · View at Google Scholar · View at Scopus
  29. J. C. E. Wang and A. M. Livingstone, “Cutting edge: CD4+ T cell help can be essential for primary CD8+ T cell responses in vivo,” Journal of Immunology, vol. 171, no. 12, pp. 6339–6343, 2003. View at Scopus
  30. C. Bourgeois, B. Rocha, and C. Tanchot, “A role for CD40 expression on CD8+ T cells in the generation of CD8+ T cell memory,” Science, vol. 297, no. 5589, pp. 2060–2063, 2002. View at Publisher · View at Google Scholar · View at Scopus
  31. D. Cassell and J. Forman, “Linked recognition of helper and cytotoxic antigenic determinants for the generation of cytotoxic T lymphocytes,” Annals of the New York Academy of Sciences, vol. 532, pp. 51–60, 1988. View at Scopus
  32. J. P. Ridge, F. Di Rosa, and P. Matzinger, “A conditioned dendritic cell can be a temporal bridge between a CD4+ T-helper and a T-killer cell,” Nature, vol. 393, no. 6684, pp. 474–478, 1998. View at Scopus
  33. S. P. Schoenberger, R. E. M. Toes, E. I. H. Van Dervoort, R. Offringa, and C. J. M. Melief, “T-cell help for cytotoxic T lymphocytes is mediated by CD40-CD4OL interactions,” Nature, vol. 393, no. 6684, pp. 480–483, 1998. View at Scopus
  34. S. R. M. Bennett, F. R. Carbone, F. Karamalis, R. A. Flavell, J. F. A. P. Miller, and W. R. Heath, “Help for cytotoxic-T-cell responses is mediated by CD4O signalling,” Nature, vol. 393, no. 6684, pp. 478–480, 1998. View at Scopus
  35. C. M. Smith, N. S. Wilson, J. Waithman et al., “Cognate CD4+ T cell licensing of dendritic cells in CD8+ T cell immunity,” Nature Immunology, vol. 5, no. 11, pp. 1143–1148, 2004. View at Publisher · View at Google Scholar · View at Scopus
  36. Y. P. Lai, C. C. Lin, W. J. Liao, C. Y. Tang, and S. C. Chen, “CD4+ T cell-derived IL-2 signals during early priming advances primary CD8+ T cell responses,” PLoS One, vol. 4, no. 11, Article ID e7766, 2009. View at Publisher · View at Google Scholar · View at Scopus
  37. K. A. Smith, “Interleukin-2: inception, impact, and implications,” Science, vol. 240, no. 4856, pp. 1169–1176, 1988. View at Scopus
  38. H. Suzuki, T. M. Kundig, C. Furlonger et al., “Deregulated T cell activation and autoimmunity in mice lacking interleukin-2 receptor β,” Science, vol. 268, no. 5216, pp. 1472–1476, 1995. View at Scopus
  39. D. M. Willerford, J. Chen, J. A. Ferry, L. Davidson, A. Ma, and F. W. Alt, “Interleukin-2 receptor α chain regulates the size and content of the peripheral lymphoid compartment,” Immunity, vol. 3, no. 4, pp. 521–530, 1995. View at Scopus
  40. H. Wagner, M. Kronke, W. Solbach, P. Scheurich, M. Röllinghoff, and K. Pfizenmaier, “6 Murine T cell subsets and interleukins: relationships between cytotoxic T cells, helper T cells and accessory cells,” Clinics in Haematology, vol. 11, no. 3, pp. 607–630, 1982. View at Scopus
  41. J. Thèze, P. M. Alzari, and J. Bertoglio, “Interleukin 2 and its receptors: recent advances and new immunological functions,” Immunology Today, vol. 17, no. 10, pp. 481–486, 1996. View at Publisher · View at Google Scholar · View at Scopus
  42. T. Taniguchi and Y. Minami, “The IL-2/IL-2 receptor system: a current overview,” Cell, vol. 73, no. 1, pp. 5–8, 1993. View at Publisher · View at Google Scholar · View at Scopus
  43. M. J. Bevan, “Helping the CD8+ T-cell response,” Nature Reviews Immunology, vol. 4, no. 8, pp. 595–602, 2004. View at Scopus
  44. M. F. Mackey, R. J. Barth Jr., and R. J. Noelle, “The role of CD40/CD154 interactions in the priming, differentiation, and effector function of helper and cytotoxic T cells,” Journal of Leukocyte Biology, vol. 63, no. 4, pp. 418–428, 1998. View at Scopus
  45. M. F. Mackey, J. R. Gunn, P. P. Ting et al., “Protective immunity induced by tumor vaccines requires interaction between CD40 and its ligand, CD154,” Cancer Research, vol. 57, no. 13, pp. 2569–2574, 1997. View at Scopus
  46. Y. C. Nesbeth, D. G. Martinez, S. Toraya et al., “CD4+ T cells elicit host immune responses to MHC class II- ovarian cancer through CCL5 secretion and CD40-mediated licensing of dendritic cells,” Journal of Immunology, vol. 184, no. 10, pp. 5654–5662, 2010. View at Publisher · View at Google Scholar · View at Scopus
  47. G. Behrens, M. Li, C. M. Smith et al., “Helper T cells, dendritic cells and CTL Immunity,” Immunology and Cell Biology, vol. 82, no. 1, pp. 84–90, 2004. View at Publisher · View at Google Scholar · View at Scopus
  48. H. Huang, X. G. Bi, J. Y. Yuan, S. L. Xu, X. L. Guo, and J. Xiang, “Combined CD4+ Th1 effect and lymphotactin transgene expression enhance CD8+ Tc1 tumor localization and therapy,” Gene Therapy, vol. 12, no. 12, pp. 999–1010, 2005. View at Publisher · View at Google Scholar · View at Scopus
  49. L. Hunziker, P. Klenerman, R. M. Zinkernagel, and S. Ehl, “Exhaustion of cytotoxic T cells during adoptive immunotherapy of virus carrier mice can be prevented by B cells or CD4+ T cells,” European Journal of Immunology, vol. 32, no. 2, pp. 374–382, 2002. View at Publisher · View at Google Scholar · View at Scopus
  50. C. N. Baxevanis, I. F. Voutsas, O. E. Tsitsilonis, A. D. Gritzapis, R. Sotiriadou, and M. Papamichail, “Tumor-specific CD4+ T lymphocytes from cancer patients are required for optimal induction of cytotoxic T cells against the autologous tumor,” Journal of Immunology, vol. 164, no. 7, pp. 3902–3912, 2000. View at Scopus
  51. R. Bos and L. A. Sherman, “CD4+ T-cell help in the tumor milieu is required for recruitment and cytolytic function of CD8+ T lymphocytes,” Cancer Research, vol. 70, no. 21, pp. 8368–8377, 2010. View at Publisher · View at Google Scholar · View at Scopus
  52. S. B. J. Wong, R. Bos, and L. A. Sherman, “Tumor-specific CD4+ T cells render the tumor environment permissive for infiltration by low-avidity CD8+ T cells,” Journal of Immunology, vol. 180, no. 5, pp. 3122–3131, 2008. View at Scopus
  53. M. L. Hwang, J. R. Lukens, and T. N. J. Bullock, “Cognate memory CD4+ T cells generated with dendritic cell priming influence the expansion, trafficking, and differentiation of secondary CD8+ T cells and enhance tumor control,” Journal of Immunology, vol. 179, no. 9, pp. 5829–5838, 2007. View at Scopus
  54. S. A. Rosenberg, R. M. Sherry, K. E. Morton et al., “Tumor progression can occur despite the induction of very high levels of self/tumor antigen-specific CD8+ T cells in patients with melanoma,” Journal of Immunology, vol. 175, no. 9, pp. 6169–6176, 2005. View at Scopus
  55. S. A. Rosenberg, J. C. Yang, D. J. Schwartzentruber et al., “Immunologic and therapeutic evaluation of a synthetic peptide vaccine for the treatment of patients with metastatic melanoma,” Nature Medicine, vol. 4, no. 3, pp. 321–327, 1998. View at Publisher · View at Google Scholar · View at Scopus
  56. S. Mukai, J. Kjærgaard, S. Shu, and G. E. Plautz, “Infiltration of tumors by systemically transferred tumor-reactive T lymphocytes is required for antitumor efficacy,” Cancer Research, vol. 59, no. 20, pp. 5245–5249, 1999. View at Scopus
  57. R. Ganss, E. Ryschich, E. Klar, B. Arnold, and G. J. Hämmerling, “Combination of T-cell therapy and trigger of inflammation induces remodeling of the vasculature and tumor eradication,” Cancer Research, vol. 62, no. 5, pp. 1462–1470, 2002. View at Scopus
  58. D. P. Assudani, R. B. V. Horton, M. G. Mathieu, S. E. B. McArdle, and R. C. Rees, “The role of CD4+ T cell help in cancer immunity and the formulation of novel cancer vaccines,” Cancer Immunology, Immunotherapy, vol. 56, no. 1, pp. 70–80, 2007. View at Publisher · View at Google Scholar · View at Scopus
  59. H. Gyobu, T. Tsuji, Y. Suzuki et al., “Generation and targeting of human tumor-specific Tc1 and Th1 cells transduced with a lentivirus containing a chimeric immunoglobulin T-cell receptor,” Cancer Research, vol. 64, no. 4, pp. 1490–1495, 2004. View at Publisher · View at Google Scholar · View at Scopus
  60. M. K. Jenkins and R. H. Schwartz, “Antigen presentation by chemically modified splenocytes induces antigen-specific T cell unresponsiveness in vitro and in vivo,” Journal of Experimental Medicine, vol. 165, no. 2, pp. 302–319, 1987. View at Scopus
  61. S. K. Babcock, R. G. Gill, D. Bellgrau, and K. J. Lafferty, “Studies on the two-signal model for T cell activation in vivo,” Transplantation Proceedings, vol. 19, no. 1, pp. 303–306, 1987. View at Scopus
  62. P. A. Van der Merwe, “The TCR triggering puzzle,” Immunity, vol. 14, no. 6, pp. 665–668, 2001. View at Publisher · View at Google Scholar · View at Scopus
  63. G. Yang, K. E. Hellstrom, M. T. Mizuno, and L. Chen, “In vitro priming of tumor-reactive cytolytic T lymphocytes by combining IL-10 with B7-CD28 costimulation,” Journal of Immunology, vol. 155, no. 8, pp. 3897–3903, 1995. View at Scopus
  64. A. Viola and A. Lanzavecchia, “T cell activation determined by T cell receptor number and tunable thresholds,” Science, vol. 273, no. 5271, pp. 104–106, 1996. View at Scopus
  65. A. Cuenca, F. Cheng, H. Wang et al., “Extra-lymphatic solid tumor growth is not immunologically ignored and results in early induction of antigen-specific T-cell anergy: dominant role of cross-tolerance to tumor antigens,” Cancer Research, vol. 63, no. 24, pp. 9007–9015, 2003. View at Scopus
  66. K. Staveley-O'Carroll, E. Sotomayor, J. Montgomery et al., “Induction of antigen-specific T cell anergy: an early event in the course of tumor progression,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 3, pp. 1178–1183, 1998. View at Publisher · View at Google Scholar · View at Scopus
  67. S. A. Quezada, T. R. Simpson, K. S. Peggs et al., “Tumor-reactive CD4+ T cells develop cytotoxic activity and eradicate large established melanoma after transfer into lymphopenic hosts,” Journal of Experimental Medicine, vol. 207, no. 3, pp. 637–650, 2010. View at Publisher · View at Google Scholar · View at Scopus
  68. D. M. Brown, “Cytolytic CD4 cells: direct mediators in infectious disease and malignancy,” Cellular Immunology, vol. 262, no. 2, pp. 89–95, 2010. View at Publisher · View at Google Scholar · View at Scopus
  69. L. Fransen, J. Van der Heyden, R. Ruysschaert, and W. Fiers, “Recombinant tumor necrosis factor: its effect and its synergism with interferon-γ on a variety of normal and transformed human cell lines,” European Journal of Cancer and Clinical Oncology, vol. 22, no. 4, pp. 419–426, 1986. View at Scopus
  70. Z. Qin and T. Blankenstein, “CD4+ T cell—mediated tumor rejection involves inhibition of angiogenesis that is dependent on IFNγ receptor expression by nonhematopoietic cells,” Immunity, vol. 12, no. 6, pp. 677–686, 2000. View at Scopus
  71. A. Corthay, D. K. Skovseth, K. U. Lundin et al., “Primary antitumor immune response mediated by CD4+ T cells,” Immunity, vol. 22, no. 3, pp. 371–383, 2005. View at Publisher · View at Google Scholar · View at Scopus
  72. A. S. Dighe, E. Richards, L. J. Old, and R. D. Schreiber, “Enhanced in vivo growth and resistance to rejection of tumor cells expressing dominant negative IFNγ receptors,” Immunity, vol. 1, no. 6, pp. 447–456, 1994. View at Scopus
  73. N. Müller-Hermelink, H. Braumüller, B. Pichler et al., “TNFR1 signaling and IFN-γ signaling determine whether T cells induce tumor dormancy or promote multistage carcinogenesis,” Cancer Cell, vol. 13, no. 6, pp. 507–518, 2008. View at Publisher · View at Google Scholar · View at Scopus
  74. C. M. Coughlin, K. E. Salhany, M. S. Gee et al., “Tumor cell responses to IFNγ affect tumorigenicity and response to IL- 12 therapy and antiangiogenesis,” Immunity, vol. 9, no. 1, pp. 25–34, 1998. View at Publisher · View at Google Scholar · View at Scopus
  75. E. M. Shevach, “CD4+CD25+ suppressor T cells: more questions than answers,” Nature Reviews Immunology, vol. 2, no. 6, pp. 389–400, 2002. View at Scopus
  76. J. F. Bach, “Regulatory T cells under scrutiny,” Nature Reviews Immunology, vol. 3, no. 3, pp. 189–198, 2003. View at Publisher · View at Google Scholar · View at Scopus
  77. J. Shimizu, S. Yamazaki, and S. Sakaguchi, “Induction of tumor immunity by removing CD25+CD4+ T cells: a common basis between tumor immunity and autoimmunity,” Journal of Immunology, vol. 163, no. 10, pp. 5211–5218, 1999. View at Scopus
  78. F. Ghiringhelli, C. Ménard, M. Terme et al., “CD4+CD25+ regulatory T cells inhibit natural killer cell functions in a transforming growth factor-β-dependent manner,” Journal of Experimental Medicine, vol. 202, no. 8, pp. 1075–1085, 2005. View at Publisher · View at Google Scholar · View at Scopus
  79. T. J. Curiel, G. Coukos, L. Zou et al., “Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival,” Nature Medicine, vol. 10, no. 9, pp. 942–949, 2004. View at Publisher · View at Google Scholar · View at Scopus
  80. U. K. Liyanage, T. T. Moore, H. G. Joo et al., “Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma,” Journal of Immunology, vol. 169, no. 5, pp. 2756–2761, 2002. View at Scopus
  81. E. Y. Woo, C. S. Chu, T. J. Goletz et al., “Regulatory CD4+CD25+ T cells in tumors from patients with early-stage non-small cell lung cancer and late-stage ovarian cancer,” Cancer Research, vol. 61, no. 12, pp. 4766–4772, 2001. View at Scopus
  82. L. R. Javia and S. A. Rosenberg, “CD4+CD25+ suppressor lymphocytes in the circulation of patients immunized against melanoma antigens,” Journal of Immunotherapy, vol. 26, no. 1, pp. 85–93, 2003. View at Publisher · View at Google Scholar · View at Scopus
  83. A. M. Wolf, D. Wolf, M. Steurer, G. Gastl, E. Gunsilius, and B. Grubeck-Loebenstein, “Increase of regulatory T cells in the peripheral blood of cancer patients,” Clinical Cancer Research, vol. 9, no. 2, pp. 606–612, 2003. View at Scopus
  84. S. J. Prasad, K. J. Farrand, S. A. Matthews, J. H. Chang, R. S. McHugh, and F. Ronchese, “Dendritic cells loaded with stressed tumor cells elicit long-lasting protective tumor immunity in mice depleted of CD4+CD25+ regulatory T cells,” Journal of Immunology, vol. 174, no. 1, pp. 90–98, 2005. View at Scopus
  85. R. P. M. Sutmuller, L. M. Van Duivenvoorde, A. Van Elsas 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,” Journal of Experimental Medicine, vol. 194, no. 6, pp. 823–832, 2001. View at Publisher · View at Google Scholar · View at Scopus
  86. E. Jones, M. Dahm-Vicker, A. K. Simon et al., “Depletion of CD25+ regulatory cells results in suppression of melanoma growth and induction of autoreactivity in mice,” Cancer Immun, vol. 2, p. 1, 2002. View at Scopus
  87. M. J. Turk, J. A. Guevara-Patiño, G. A. Rizzuto, M. E. Engelhorn, and A. N. Houghton, “Concomitant tumor immunity to a poorly immunogenic melanoma is prevented by regulatory T cells,” Journal of Experimental Medicine, vol. 200, no. 6, pp. 771–782, 2004. View at Publisher · View at Google Scholar · View at Scopus
  88. P. A. Antony, C. A. Piccirillo, A. Akpinarli et al., “CD8+ T cell immunity against a tumor/self-antigen is augmented by CD4+ T helper cells and hindered by naturally occurring T regulatory cells,” Journal of Immunology, vol. 174, no. 5, pp. 2591–2601, 2005. View at Scopus