Agonistic Anti‐4‐1BB Antibody Promotes the Expansion of Natural Regulatory T Cells While Maintaining Foxp3 Expression

Zhang, P.; Gao, Fei; Wang, Q.; Wang, X.; Zhu, Faliang; Hong, Chun Pyo; Sun, Wei; Zhang, L.

doi:10.1111/j.1365-3083.2007.01994.x

Cited by 58 publications

(54 citation statements)

References 24 publications

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“…Our results do not support other data that have recently reported that signals through 4-1BB may inhibit Treg (32). On the contrary, more reliable data have been published suggesting that signals through 4-1BB may serve in a rather agonistic way (33)(34)(35). The exact mechanisms particularly in in vivo systems may be difficult to assess because 4-1BB has been demonstrated to be a potent stimulator particularly for conventional CD8 + T cells as well.…”

Section: Discussioncontrasting

confidence: 99%

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A Converse 4-1BB and CD40 Ligand Expression Pattern Delineates Activated Regulatory T Cells (Treg) and Conventional T Cells Enabling Direct Isolation of Alloantigen-Reactive Natural Foxp3+ Treg

Schoenbrunn

Frentsch

Köhler

et al. 2012

The Journal of Immunology

115

103

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Natural regulatory T cells (nTreg) play a central role in the induction and maintenance of immunological tolerance. Experimental transplant models and recent clinical trials demonstrate that nTreg can control alloreactivity. To upgrade Treg-based cell therapies to a selective suppression of undesired immune reactions, only the transfer of Ag-specific nTreg represents the appropriate therapeutic option. However, Ag-specific nTreg are present at extremely low frequencies in the periphery, and so far appropriate surface markers for their precise identification are missing. In this study, we demonstrate that activated nTreg and activated conventional T cells differ in their 4-1BB and CD40 ligand (CD40L) expression signatures, allowing a clear dissection from each other. Based on the expression of 4-1BB and absence of CD40L expression, human alloantigen-reactive Foxp3+ nTreg can be directly isolated from MLR cultures with high purity. Alloantigen-reactive 4-1BB+CD40L− nTreg were characterized by a completely demethylated Treg-specific demethylated region and showed alloantigen-specific suppressive properties superior to polyclonal Treg. Importantly, isolated 4-1BB+CD40L− nTreg maintain the nTreg phenotype and alloantigen-reactivity after in vitro expansion. Our results offer the possibility to simultaneously analyze Ag-specific nTreg and conventional T cells, and to establish cellular therapies with Ag-specific nTreg aiming at a specific inhibition of unwanted immunity.

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Section: Discussioncontrasting

confidence: 99%

“…This may be relevant considering that 4-1BB signaling can modulate the activation of CD4 + CD25 + Treg (34,35). It has been shown that the peripheral Treg pool comprises a complex mixture of Treg subpopulations (37) with the major classification into thymus-derived nTreg and peripherally iTreg.…”

Section: Discussionmentioning

confidence: 99%

A Converse 4-1BB and CD40 Ligand Expression Pattern Delineates Activated Regulatory T Cells (Treg) and Conventional T Cells Enabling Direct Isolation of Alloantigen-Reactive Natural Foxp3+ Treg

Schoenbrunn

Frentsch

Köhler

et al. 2012

The Journal of Immunology

115

103

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“…In addition to CTLA-4 and PD-1, expression of 4-1BB and KLRG1 has been associated with enhanced Treg function (17,18). In each case, we found that combination blockade of the CTLA-4 and PD-1 pathways significantly decreased the fraction of Tregs expressing the relevant activation marker (Fig.…”

Section: Combination Coinhibitory Receptor Blockade Decreases Expressmentioning

confidence: 63%

PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors

Curran

Montalvo

Yagita

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

1,643

1,304

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Vaccination with irradiated B16 melanoma cells expressing either GM-CSF (Gvax) or Flt3-ligand (Fvax) combined with antibody blockade of the negative T-cell costimulatory receptor cytotoxic T-lymphocyte antigen-4 (CTLA-4) promotes rejection of preimplanted tumors. Despite CTLA-4 blockade, T-cell proliferation and cytokine production can be inhibited by the interaction of programmed death-1 (PD-1) with its ligands PD-L1 and PD-L2 or by the interaction of PD-L1 with B7-1. Here, we show that the combination of CTLA-4 and PD-1 blockade is more than twice as effective as either alone in promoting the rejection of B16 melanomas in conjunction with Fvax. Adding αPD-L1 to this regimen results in rejection of 65% of preimplanted tumors vs. 10% with CTLA-4 blockade alone. Combination PD-1 and CTLA-4 blockade increases effector T-cell (Teff) infiltration, resulting in highly advantageous Teff-to-regulatory T-cell ratios with the tumor. The fraction of tumor-infiltrating Teffs expressing CTLA-4 and PD-1 increases, reflecting the proliferation and accumulation of cells that would otherwise be anergized. Combination blockade also synergistically increases Teff-to-myeloid-derived suppressor cell ratios within B16 melanomas. IFN-γ production increases in both the tumor and vaccine draining lymph nodes, as does the frequency of IFN-γ/TNF-α double-producing CD8 + T cells within the tumor. These results suggest that combination blockade of the PD-1/ PD-L1-and CTLA-4-negative costimulatory pathways allows tumorspecific T cells that would otherwise be inactivated to continue to expand and carry out effector functions, thereby shifting the tumor microenvironment from suppressive to inflammatory.he interaction between the T-cell receptor complex (TCR) and antigenic peptides bound in surface MHC molecules provides the specificity that defines adaptive T-cell immunity. In addition to TCR activation, costimulation via ligation of the coreceptor CD28 on T cells by B7 molecules on antigenpresenting cells (APCs) is required for optimal T-cell activation (1). Once mobilized, however, T cells begin to express other members of the CD28/B7 receptor family that attenuate the immune response through inhibition of proliferation and cytokine production (2). Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is rapidly up-regulated following T-cell activation and binds to B7 molecules with a higher affinity than does CD28. The receptor programmed death-1 (PD-1) is also expressed on T cells following activation, where, on binding to its ligands PD-L1 and PD-L2, it promotes T-cell anergy, apoptosis, and exhaustion. Recently, an additional coinhibitory ligand/receptor interaction has been described that involves binding of PD-L1 on T cells to B7-1 on APCs or vice versa (3). Although the existence of so many layers of T-cell inhibition may seem surprising, the severe and sometimes fatal autoimmunity that results when even one of these pathways is disrupted attests to their necessity.Malignant transformation was classically defined by the ability to avoid the norm...

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“…The TNFRSF members GITR and OX40, which we observed to be expressed by Tregs ( Figure 1A), affect Treg activity and proliferation (21)(22)(23)(24)(25)(26)(27). There are also reports that stimulation of Tregs by 4-1BB can modulate both activity and proliferation of these cells (28,29). Furthermore, stimulation of CD4 + FoxP3 -cells by TNFRSF member CD27 (also known as TNFRSF7) has been reported to induce FoxP3 expression (30).…”

Section: Tnfr25 Is Highly Expressed By Tregs To Our Knowledge Therementioning

confidence: 65%

Therapeutic Treg expansion in mice by TNFRSF25 prevents allergic lung inflammation

Schreiber¹,

Wolf²,

Tsai³

et al. 2010

J. Clin. Invest.

142

188

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TNF receptor superfamily member 25 (TNFRSF25; also known as DR3, and referred to herein as TNFR25) is constitutively and highly expressed by CD4 + FoxP3 + Tregs. However, its function on these cells has not been determined. Here we used a TNFR25-specific agonistic monoclonal antibody, 4C12, to study the effects of TNFR25 signaling on Tregs in vivo in mice. Signaling through TNFR25 induced rapid and selective expansion of preexisting Tregs in vivo such that they became 30%-35% of all CD4 + T cells in the peripheral blood within 4 days. TNFR25-induced Treg proliferation was dependent upon TCR engagement with MHC class II, IL-2 receptor, and Akt signaling, but not upon costimulation by CD80 or CD86; it was unaffected by rapamycin. TNFR25-expanded Tregs remained highly suppressive ex vivo, and Tregs expanded by TNFR25 in vivo were protective against allergic lung inflammation, a mouse model for asthma, by reversing the ratio of effector T cells to Tregs in the lung, suppressing IL-13 and Th2 cytokine production, and blocking eosinophil exudation into bronchoalveolar fluid. Our studies define what we believe to be a novel mechanism for Treg control and important functions for TNFR25 in regulating autoaggression that balance its known role in enhancing autoimmunity.

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Agonistic Anti‐4‐1BB Antibody Promotes the Expansion of Natural Regulatory T Cells While Maintaining Foxp3 Expression

Cited by 58 publications

References 24 publications

A Converse 4-1BB and CD40 Ligand Expression Pattern Delineates Activated Regulatory T Cells (Treg) and Conventional T Cells Enabling Direct Isolation of Alloantigen-Reactive Natural Foxp3+ Treg

A Converse 4-1BB and CD40 Ligand Expression Pattern Delineates Activated Regulatory T Cells (Treg) and Conventional T Cells Enabling Direct Isolation of Alloantigen-Reactive Natural Foxp3+ Treg

PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors

Therapeutic Treg expansion in mice by TNFRSF25 prevents allergic lung inflammation

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