T Helper Cell Type 1–associated and Cytotoxic T Lymphocyte–mediated Tumor Immunity Is Impaired in Interleukin 4–deficient Mice

Schüler, Thomas; Qin, Zhihai; Ibe, Sabrina; Noben-Trauth, Nancy; Blankenstein, Thomas

doi:10.1084/jem.189.5.803

Cited by 148 publications

(125 citation statements)

References 44 publications

(53 reference statements)

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“…[30][31][32] Of several cytokines whose presence affects tumor growth, IL-4 appears to be very potent. Tumor cells secreting a substantial amount of IL-4 are unable to form tumors and induce systemic immunity.…”

Section: Discussionmentioning

confidence: 99%

Tumor cells expressing membrane-bound form of IL-4 induce antitumor immunity

Kim

Sonn

et al. 2000

Gene Ther

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Local cytokine concentrations are required for inhibition of tumor growth with less toxic side-effects. However, genetically engineered tumor cells secreting cytokines still induce toxicity and activate bystander cells. To circumvent such problems, membrane-bound forms of IL-4 (IL-4m) were expressed on MethA fibrosarcoma tumor cells. Chimeric forms of IL-4 with the type I transmembrane protein CD4 or type II transmembrane protein TNF were designed to express IL-4 in opposite orientations on the tumor cell surface. The IL-4m on tumor clones was able to support cell growth of the IL-4 dependent cytotoxic cell line (CT.4S) and

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Section: Discussionmentioning

confidence: 99%

Tumor cells expressing membrane-bound form of IL-4 induce antitumor immunity

Kim

Sonn

et al. 2000

Gene Ther

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“…IFN-c, GM-CSF, TNF-a and IL-4 are T cell-derived cytokines thought to be involved in promoting IL-12p70 production by DC [14,15,[26][27][28]. We investigated whether these factors were involved in our system.…”

Section: Cd8 T Cell-mediated Il-12p70 Production Is Dependent On Ifn-cmentioning

confidence: 99%

“…Increasing the CD8 T cell-to-DC ratio in culture proportionately increased the amount of IL-12p70 produced by DC. These results indicate that CD8 T cell priming of DC for IL-12p70 was MHC class I-peptide (K b /OVA 257-264 )-specific and CD8 T cell-dependent.CD8 T cell-mediated IL-12p70 production is dependent on IFN-c IFN-c, GM-CSF, TNF-a and IL-4 are T cell-derived cytokines thought to be involved in promoting IL-12p70 production by DC [14,15,[26][27][28]. We investigated whether these factors were involved in our system.…”

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confidence: 99%

CD40L‐expressing CD8 T cells prime CD8α⁺ DC for IL‐12p70 production

et al. 2008

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CD8a + DC are implicated as the principle DC subset for cross-presentation and crosspriming of cytotoxic CD8 T cell responses. In this study, we demonstrate another unique facet of the CD8a + DC and CD8 T cell relationship, by showing that CD8 T cells reciprocally activate CD8a + DC, but not CD8a -DC, for IL-12p70 production, the key Th1-promoting cytokine. This effect was observed during an antigen-specific interaction between DC and activated CD8 T cells, along with secondary TLR stimulation of DC by LPS. Activated CD8 T cells use a combination of IFN-c and CD40L, which is rapidly up-regulated poststimulation, to prime DC for IL-12p70 production during an antigen-specific response. Our results suggest that the interaction between CD8a + DC and antigen-primed CD8 T cells may form an important component of Th1-mediated immunity through the induction of IL-12p70. Key words: CD8 T cells Á Dendritic cells Á IL-12p70Introduction DC are essential for the activation and polarization of T cells during an adaptive immune response [1,2]. DC respond to stimulatory signals from microbes and inflammatory mediators and mature into professional antigen-presenting cells that prime the adaptive immune system [3,4]. DC activity is also influenced through direct and indirect interaction with other effector immune cells, which results in the delivery of "feedback" signals that can influence the activation status of the DC and thus the outcome of the adaptive immune response [5][6][7]. CD8 T cells are principally known for their role in cytotoxic killing. However, their ability to promote Th1 responses has also been described. In vivo, CD8 T cells have been shown to be essential for the induction of protective Th1 responses against microbial infections [8][9][10]. Likewise, CD8 T cells can also inhibit the development of allergic Th2 IgE responses [11,12]. CD8 T cells can have a direct impact on DC during their interaction, inducing DC to mature [13], and enhancing their Th1-polarizing capabilities by augmenting their ability to produce 14,15].IL-12p70 is a heterodimeric pro-inflammatory cytokine that plays a central role in Th1 immunity, acting on T cells and NK cells by inducing proliferation, cytotoxic function and IFN-c production [16]. IL-12p70 production by DC during T cell priming is crucial for the development of Th1 responses [16][17][18]. Hence, control of DC IL-12p70 production is important for the development of Th1 immunity.Previous reports on CD8 T cell-mediated IL-12p70 production utilized DC generated from monocytes or bone marrow progenitors using 14,15]. These DC are now thought to appear only under inflammatory conditions [19]. They differ markedly from DC that reside in lymphoid organs, and hence do not necessarily reflect events that occur with lymphoid resident DC. Splenic DC comprise of a heterogeneous population of cells with different phenotypes and functional characteristics [20]. It is unknown whether CD8 T cells could possibly modulate IL-12p70 production with splenic resident DC, or whether CD8 T cellme...

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“…Cross-inhibitory effects of IL-4 and IFN-g have been reported mainly in vitro or in the late phase of the immune response to chronic antigen exposure. 35 Whether an immune response is predominantly Th1 or Th2 seems to depend on a number of variables (mouse strain, kind of tumor, amount of tumor antigen, and amount of cytokine 36,37 ). From our results, combination therapy with IL-4 and IFN-a may be a candidate for clinical cancer therapy.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-4 gene transduced tumor cells promote a potent tumor-specific Th1-type response in cooperation with interferon-α transduction

et al. 2005

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To investigate antitumor mechanisms in interleukin (IL)-4 therapy, we established an IL-4-overexpressing MC38 murine colorectal cancer cell line (MC38-IL4). As a therapy against established tumors, MC38-IL4 cells were inoculated contralaterally 7 days after wild-type (MC38-WT) cells had been injected, significantly reducing growth of wild-type tumors (P ¼ 0.030). Immunohistochemical analysis showed numerous granulocytes infiltrating wild-type tumors of MC38-IL4-inoculated mice. Injection of MC38-IL4 cells in leukocytedepleted mice confirmed that granulocytes were involved in IL-4-related primary antitumor effects. Inoculation of MC38-WT in leukocyte-depleted mice initially injected with MC38-IL4 suggested that T cells contributed to the antitumor effects. To investigate tumor-specific responses, we stimulated splenocytes of MC38-immune mice with MC38-IL4 cells in vitro, resulting in MC38-specific lysis (57.577.2%, effector to target ratio ¼ 20). Treatment of established wild-type tumors with MC38-IL4 in combination with interferon (IFN)-a-overexpressing MC38 cells (MC38-IFNa) significantly reduced the growth of wild-type tumors (P ¼ 0.009). In vitro IFN-g production by splenocytes from mice injected with both MC38-IL4 and -IFNa was greatly enhanced in comparison with MC38-IL4 alone, while IL-10 production was not increased. Thus, granulocytes concern early antitumor effects of IL-4 therapy. Subsequently, IL-4 induces longlasting, tumor-specific immune responses. IL-4 appears to promote a T-helper 1-type antitumor immune response, which is enhanced in cooperation with IFN-a. Gene Therapy (2005) 12, 733-741.

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T Helper Cell Type 1–associated and Cytotoxic T Lymphocyte–mediated Tumor Immunity Is Impaired in Interleukin 4–deficient Mice

Cited by 148 publications

References 44 publications

Tumor cells expressing membrane-bound form of IL-4 induce antitumor immunity

Tumor cells expressing membrane-bound form of IL-4 induce antitumor immunity

CD40L‐expressing CD8 T cells prime CD8α⁺ DC for IL‐12p70 production

Interleukin-4 gene transduced tumor cells promote a potent tumor-specific Th1-type response in cooperation with interferon-α transduction

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T Helper Cell Type 1–associated and Cytotoxic T Lymphocyte–mediated Tumor Immunity Is Impaired in Interleukin 4–deficient Mice

Cited by 148 publications

References 44 publications

Tumor cells expressing membrane-bound form of IL-4 induce antitumor immunity

Tumor cells expressing membrane-bound form of IL-4 induce antitumor immunity

CD40L‐expressing CD8 T cells prime CD8α+ DC for IL‐12p70 production

Interleukin-4 gene transduced tumor cells promote a potent tumor-specific Th1-type response in cooperation with interferon-α transduction

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CD40L‐expressing CD8 T cells prime CD8α⁺ DC for IL‐12p70 production