Systemic 4-1BB activation induces a novel T cell phenotype driven by high expression of Eomesodermin

Curran, Michael A.; Geiger, Theresa L.; Montalvo, Welby; Kim, Myoungjoo; Reiner, Steven L.; Al‐Shamkhani, Aymen; Sun, Joseph C.; Allison, James P.

doi:10.1084/jem.20121190

Cited by 148 publications

(178 citation statements)

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“…It has previously been reported that the cytotoxic potential of tumor-specific CD4 + killer T cells depends on transcription factor Eomes expression (6). In addition, it was demonstrated that Eomes plays an important role in initiating granzyme production in FIGURE 5.…”

Section: Discussionmentioning

confidence: 94%

“…Because CD137 is more prominently expressed on CD8 + T cells than CD4 + T cells, most immunotherapy studies have focused on the impact of anti-CD137 on CD8 + T cell immunity (4). However, a recent study demonstrated that, in addition to improved CD8 + T cell responses in B16 Melanoma, anti-CD137 treatment also drove differentiation of CD4 + T cells into cytotoxic effectors (6). This cytotoxicity of CD4 T cells was dependent on the regulatory T-box transcription factor Eomesodermin (Eomes) and mediated by KLRG-1 + terminally differentiated effector T cells (6).…”

mentioning

confidence: 99%

“…However, a recent study demonstrated that, in addition to improved CD8 + T cell responses in B16 Melanoma, anti-CD137 treatment also drove differentiation of CD4 + T cells into cytotoxic effectors (6). This cytotoxicity of CD4 T cells was dependent on the regulatory T-box transcription factor Eomesodermin (Eomes) and mediated by KLRG-1 + terminally differentiated effector T cells (6). Curran et al (6) nicely showed that effector KLRG-1 + Eomes + CD4 + and CD8 + T cells, generated by anti2CD137 treatment, enhanced tumor-specific cytotoxicity and in turn promoted tumor immunity.…”

mentioning

confidence: 99%

“…This cytotoxicity of CD4 T cells was dependent on the regulatory T-box transcription factor Eomesodermin (Eomes) and mediated by KLRG-1 + terminally differentiated effector T cells (6). Curran et al (6) nicely showed that effector KLRG-1 + Eomes + CD4 + and CD8 + T cells, generated by anti2CD137 treatment, enhanced tumor-specific cytotoxicity and in turn promoted tumor immunity. Because the majority of cytotoxic antitumor immunity is mediated by CD8 + T cell response, it remains unknown how much cytotoxic CD4 + T cells actually contribute to tumor rejection in such immune studies and in particular after treatment with CD137 agonist.…”

mentioning

confidence: 99%

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CD137 Agonist Therapy Can Reprogram Regulatory T Cells into Cytotoxic CD4+ T Cells with Antitumor Activity

Akhmetzyanova

Zelinskyy

Littwitz-Salomon

et al. 2016

The Journal of Immunology

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Recent successes in immune therapeutic strategies aimed to improve control over tumor growth have sparked hope that long-lived control of cancer through stimulation of the immune system can be possible. However, the underlying immunological mechanisms that are induced by immunotherapeutic strategies are not well understood. In this study, we used the highly immunogenic Friend virus–induced FBL-3 tumor as a model to study the mechanisms of immunological tumor control by CD4+ T cells in the course of CD137 (4-1BB) agonist immunotherapy in the absence of a CD8 T cell response. We demonstrate that treatment with a CD137 agonist resulted in complete FBL-3 tumor regression in CD8+ T cell–deficient mice. CD137 signaling enhanced the production of proinflammatory cytokines and cytotoxic molecules in tumor-specific CD4+ T cells. Interestingly, a subset of CD4+Foxp3+ regulatory T cells was reprogrammed to eliminate immunogenic virus-induced tumor cells in response to CD137 agonist treatment. These cells expressed markers characteristic for Th cells (CD154) and produced the cytokine TNF-α or the T-box transcriptional factor Eomesodermin and granzyme B without loss of Foxp3 expression. Foxp3 Eomes double-positive CD4+ T cells were capable of eliminating immunogenic virus-induced tumor cells in vivo. Thus, our data show that tumor-induced Foxp3+CD4+ T cells can be reprogrammed into cytotoxic effector cells upon therapeutic costimulatory signaling and restore antitumor immunity.

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Section: Discussionmentioning

confidence: 94%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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CD137 Agonist Therapy Can Reprogram Regulatory T Cells into Cytotoxic CD4+ T Cells with Antitumor Activity

Akhmetzyanova

Zelinskyy

Littwitz-Salomon

et al. 2016

The Journal of Immunology

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“…Among these, the T-bet paralogue eomesodermin (Eomes) has been shown to affect Th polarization (8)(9)(10)(11). Eomes is a T-box transcription factor initially described as a crucial player in embryonic development, and Eomes-deficient mice die early during embryonic development (12,13).…”

Section: T He Cd4 + T Cells Coordinate Different Types Of Immunementioning

confidence: 99%

Eomesodermin Expression in CD4+ T Cells Restricts Peripheral Foxp3 Induction

Lupar¹,

Brack

Garnier

et al. 2015

The Journal of Immunology

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CD4+ T cells polarize into effector Th subsets characterized by signature transcription factors and cytokines. Although T-bet drives Th1 responses and represses the alternative Th2, Th17, and Foxp3+ regulatory T cell fates, the role of the T-bet–related transcription factor eomesodermin (Eomes) in CD4+ T cells is less well understood. In this study, we analyze the expression and effects of Eomes in mouse CD4+ T lymphocytes. We find that Eomes is readily expressed in activated CD4+ Th1 T cells in vivo. Eomes+ CD4+ T cells accumulated in old mice, under lymphopenic conditions in a T cell transfer model of colitis, and upon oral Ag administration. However, despite its expression, genetic deletion of Eomes in CD4+ T cells did not impact on IFN-γ production nor increase Th2 or Th17 responses. In contrast, Eomes deficiency favored the accumulation of Foxp3+ cells in old mice, after in vivo differentiation of Eomes-deficient naive CD4+ T cells, and in response to oral Ag in a cell-intrinsic way. Enforced Eomes expression during in vitro regulatory T cell induction also reduced Foxp3 transcription. Likewise, bystander Eomes-deficient CD4+ T cells were more efficient at protecting from experimental autoimmune encephalitis compared with wild-type CD4+ T cells. This enhanced capacity of Eomes-deficient CD4+ T cells to inhibit EAE in trans was associated with an enhanced frequency of Foxp3+ cells. Our data identify a novel role for Eomes in CD4+ T cells and indicate that Eomes expression may act by limiting Foxp3 induction, which may contribute to the association of EOMES to susceptibility to multiple sclerosis.

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CD4⁺ Cytotoxic T Lymphocytes in Cancer Immunity and Immunotherapy

Wang

et al. 2022

Advanced Biology

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CD4+ T cells have the ability to differentiate into relatively specialized effector subsets after exposure to innate immune signals. The remarkable plasticity of CD4+ T cells is required to achieve immune responses in different tissues and against various pathogens. Numerous studies have shown that CD4+ T cells can play direct and indispensable roles in protective immunity by killing infected or transformed cells. Although the lineage decision of commitment to the CD4+ or CD8+ cell lineage is once thought to be inflexible, the identification of antigen‐experienced CD4+ T cells with cytotoxic activity suggests the existence of unexpected plasticity for these cells. The recognition of CD4+ cytotoxic T lymphocytes (CTLs) and the mechanisms driving the differentiation of this particular cell subset create opportunities to explore the roles of these effector cells in protective immunity and immune‐related pathology. CD4+ CTLs are proven to play a protective role in antiviral immunity. Here, the latest investigations on the phenotypic and functional features of CD4+ CTLs and their roles in antitumor immunity and immunotherapy are briefly reviewed.

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Systemic 4-1BB activation induces a novel T cell phenotype driven by high expression of Eomesodermin

Abstract: Anti–4-1BB treatment of tumor-bearing or intracellular pathogen infected mice generates a population of Eomes+KLRG1+ tumor infiltrating T cells that have enhanced cytotoxic activity.

Cited by 148 publications

References 50 publications

CD137 Agonist Therapy Can Reprogram Regulatory T Cells into Cytotoxic CD4+ T Cells with Antitumor Activity

CD137 Agonist Therapy Can Reprogram Regulatory T Cells into Cytotoxic CD4+ T Cells with Antitumor Activity

Eomesodermin Expression in CD4+ T Cells Restricts Peripheral Foxp3 Induction

CD4⁺ Cytotoxic T Lymphocytes in Cancer Immunity and Immunotherapy

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Systemic 4-1BB activation induces a novel T cell phenotype driven by high expression of Eomesodermin

Abstract: Anti–4-1BB treatment of tumor-bearing or intracellular pathogen infected mice generates a population of Eomes+KLRG1+ tumor infiltrating T cells that have enhanced cytotoxic activity.

Cited by 148 publications

References 50 publications

CD137 Agonist Therapy Can Reprogram Regulatory T Cells into Cytotoxic CD4+ T Cells with Antitumor Activity

CD137 Agonist Therapy Can Reprogram Regulatory T Cells into Cytotoxic CD4+ T Cells with Antitumor Activity

Eomesodermin Expression in CD4+ T Cells Restricts Peripheral Foxp3 Induction

CD4+ Cytotoxic T Lymphocytes in Cancer Immunity and Immunotherapy

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CD4⁺ Cytotoxic T Lymphocytes in Cancer Immunity and Immunotherapy