OX40-Mediated Differentiation to Effector Function Requires IL-2 Receptor Signaling but Not CD28, CD40, IL-12Rβ2, or T-bet

Williams, Cortny A.; Murray, Susan; Weinberg, Andrew D.; Parker, David C.

doi:10.4049/jimmunol.178.12.7694

Cited by 33 publications

(35 citation statements)

References 44 publications

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“…In contrast, IFN-␥ production was not affected by the absence of IL-2 signaling, which is consistent with the ability of CD8 T cells to develop the capacity to produce IFN-␥ in an IL-2-independent manner (42). Interestingly, recent work from Williams et al (43) has demonstrated that anti-OX40 treatment can drive CD4 T cells into Th1 effector cells via an IL-2-dependent mechanism. In contrast to the results obtained with CD8 T cells, the OX40-mediated increase in CD4 T cell-specific IFN-␥ production was dependent upon IL-2 signaling.…”

Section: Discussionsupporting

confidence: 74%

Defects in the Acquisition of CD8 T Cell Effector Function after Priming with Tumor or Soluble Antigen Can Be Overcome by the Addition of an OX40 Agonist

Redmond

Gough

Charbonneau

et al. 2007

The Journal of Immunology

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Several members of the TNFR superfamily, including OX40 (CD134), 4-1BB (CD137), and CD27 provide critical costimulatory signals that promote T cell survival and differentiation in vivo. Although several studies have demonstrated that OX40 engagement can enhance CD4 T cell responses, the mechanisms by which OX40-mediated signals augment CD8 T cell responses are still unclear. Previously, we and others have shown that OX40 engagement on Ag-specific CD8 T cells led to increased CD8 T cell expansion, survival, and the generation of greater numbers of long-lived memory cells. Currently, we demonstrate that provision of an OX40 agonist during the activation of naive CD8 T cells primed in vivo with either soluble or tumor-associated Ag significantly augments granzyme B expression and CD8 T cell cytolytic function through an IL-2-dependent mechanism. Furthermore, augmented CTL function required direct engagement of OX40 on the responding CD8 T cells and was associated with increased antitumor activity against established prostate tumors and enhanced the survival of tumor-bearing hosts. Thus, in the absence of danger signals, as is often the case in a tumor-bearing host, provision of an OX40 agonist can overcome defective CD8 T cell priming and lead to a functional antitumor response in vivo.

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Section: Discussionsupporting

confidence: 74%

Defects in the Acquisition of CD8 T Cell Effector Function after Priming with Tumor or Soluble Antigen Can Be Overcome by the Addition of an OX40 Agonist

Redmond

Gough

Charbonneau

et al. 2007

The Journal of Immunology

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“…Although this data seems to be at odds with the premise that IL-12 drives a Th1 response, previous studies have shown that IL-12 (p35)-deficient mice infected with lymphocytic choriomeningitis virus produce equivalent levels of IFN-␥ when compared with wild-type mice (31). Furthermore, a recent study demonstrated IL-12R␤2 did not play a significant role in the differentiation of Ag-specific CD4 T cells following OX40 engagement (32). Therefore, in anti-OX40-stimulated CD4 T cells, IL-12 appears to be more important for survival than Th1 differentiation.…”

Section: Il-12 Signaling Is Critical For Ox40-enhanced Cd4 T Cell Surmentioning

confidence: 85%

IL-12 Is Required for Anti-OX40-Mediated CD4 T Cell Survival

Ruby

Montler

Zheng

et al. 2008

The Journal of Immunology

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Engagement of OX40 greatly improves CD4 T cell function and survival. Previously, we showed that both OX40 engagement and CTLA-4 blockade led to enhanced CD4 T cell expansion, but only OX40 signaling increased survival. To identify pathways associated with OX40-mediated survival, the gene expression of Ag-activated CD4 T cells isolated from mice treated with anti-OX40 and -CTLA-4 was compared. This comparison revealed a potential role for IL-12 through increased expression of the IL-12R-signaling subunit (IL-12Rβ2) on T cells activated 3 days previously with Ag and anti-OX40. The temporal expression of IL-12Rβ2 on OX40-stimulated CD4 T cells was tightly regulated and peaked ∼4–6 days after initial activation/expansion, but before the beginning of T cell contraction. IL-12 signaling, during this window of IL-12Rβ2 expression, was required for enhanced T cell survival and survival was associated with STAT4-specific signaling. The findings from these observations were exploited in several different mouse tumor models where we found that the combination of anti-OX40 and IL-12 showed synergistic therapeutic efficacy. These results may lead to the elucidation of the molecular pathways involved with CD4 T cell survival that contribute to improved memory, and understanding of these pathways could lead to greater efficacy of immune stimulatory Abs in tumor-bearing individuals.

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“…Although TCR stimulation is necessary to up-regulate OX40, additional signals are required for inducing optimal OX40 expression. For example, CD28 signaling can contribute to OX40-mediated co-stimulation [8], [9], although CD28 itself is not required for the generation of OX40-dependent responses [10], [11]. Since CD28 ligation leads to increased IL-2Ralpha (CD25) expression and IL-2 production [12], it is unclear whether CD28-B7 signaling contributes to OX40-mediated co-stimulation directly or through an IL-2-dependent mechanism.…”

Section: Introductionmentioning

confidence: 99%

Dual Anti-OX40/IL-2 Therapy Augments Tumor Immunotherapy via IL-2R-Mediated Regulation of OX40 Expression

et al. 2012

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The provision of T cell co-stimulation via members of the TNFR super-family, including OX40 (CD134) and 4-1BB (CD137), provides critical signals that promote T cell survival and differentiation. Recent studies have demonstrated that ligation of OX40 can augment T cell-mediated anti-tumor immunity in pre-clinical models and more importantly, OX40 agonists are under clinical development for cancer immunotherapy. OX40 is of particular interest as a therapeutic target as it is not expressed on naïve T cells but rather, is transiently up-regulated following TCR stimulation. Although TCR engagement is necessary for inducing OX40 expression, the downstream signals that regulate OX40 itself remain unclear. In this study, we demonstrate that OX40 expression is regulated through a TCR and common gamma chain cytokine-dependent signaling cascade that requires JAK3-mediated activation of the downstream transcription factors STAT3 and STAT5. Furthermore, combined treatment with an agonist anti-OX40 mAb and IL-2 augmented tumor immunotherapy against multiple tumor types. Dual therapy was also able to restore the function of anergic tumor-reactive CD8 T cells in mice with long-term well-established (>5 wks) tumors, leading to increased survival of the tumor-bearing hosts. Together, these data reveal the ability of TCR/common gamma chain cytokine signaling to regulate OX40 expression and demonstrate a novel means of augmenting cancer immunotherapy by providing dual anti-OX40/common gamma chain cytokine-directed therapy.

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OX40-Mediated Differentiation to Effector Function Requires IL-2 Receptor Signaling but Not CD28, CD40, IL-12Rβ2, or T-bet

Cited by 33 publications

References 44 publications

Defects in the Acquisition of CD8 T Cell Effector Function after Priming with Tumor or Soluble Antigen Can Be Overcome by the Addition of an OX40 Agonist

Defects in the Acquisition of CD8 T Cell Effector Function after Priming with Tumor or Soluble Antigen Can Be Overcome by the Addition of an OX40 Agonist

IL-12 Is Required for Anti-OX40-Mediated CD4 T Cell Survival

Dual Anti-OX40/IL-2 Therapy Augments Tumor Immunotherapy via IL-2R-Mediated Regulation of OX40 Expression

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