Critical Role of Regulatory T Cells in Th17-Mediated Minor Antigen-Disparate Rejection

Vokaer, Benoît; Rompaey, Nicolas Van; Lemaître, Philippe; Lhommé, Frédéric; Kubjak, Carole; Benghiat, Fleur Samantha; Iwakura, Yoichiro; Pétein, Michel; Field, Kenneth A.; Goldman, Michel; Moine, Alaín Le; Charbonnier, Louis-Marie

doi:10.4049/jimmunol.0903961

Cited by 57 publications

(48 citation statements)

References 53 publications

(53 reference statements)

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“…However, there is a certain degree of plasticity that Tregs retain, and under specific conditions they may adopt a proinflammatory phenotype (32). This phenotype includes a helper-like role and has been observed in different models, including vaccination (33), tumors (34), or graft rejection (35). In particular, Addey et al (34) demonstrated that, in the murine urothelial carcinoma model, Tregs upregulated genes characteristic for a Th cell phenotype, such as proinflammatory cytokines.…”

Section: Discussionmentioning

confidence: 99%

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: 99%

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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“…IL-17 was reported to promote the maturation of dendritic cell progenitors (29) and graft inflammation (30) in separate models of murine cardiac allograft rejection, thus suggesting its potential role in facilitating the acute rejection response. Increased expression of IL-17 mRNA and protein has been demonstrated during the early stages of renal allograft rejection in both humans (31,32) and animal models (33,34). Despite circumstantial evidence implicating a role for IL-17 in the early phases of renal allograft rejection, the role of IL-17 deficiency has not been previously examined in an animal model of renal allograft rejection.…”

Section: Introductionmentioning

confidence: 99%

IL-17 Deficiency Attenuates Allograft Injury and Prolongs Survival in a Murine Model of Fully MHC-Mismatched Renal Allograft Transplantation

Kwan

Chadban

et al. 2015

American Journal of Transplantation

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“…+ T cells, which do not express cytokines, might be important for the risk of graft-versus-host disease after bone marrow transplantation [37][38][39], but probably have little impact on the risk for acute rejection after kidney transplantation [40]. Currently, we are investigating how alloreactive CD137 + T cells develop following kidney transplantation, and whether or not the presence of certain subsets of alloreactive T cells are related specifically to the risk for acute rejection after kidney transplantation.…”

Section: Cd4mentioning

confidence: 99%

Activation-induced CD137 is a fast assay for identification and multi-parameter flow cytometric analysis of alloreactive T cells

Litjens

Wit

Baan

et al. 2013

Clinical and Experimental Immunology

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SummaryDetection and isolation of viable alloreactive T cells at the single-cell level requires a cell surface marker induced specifically upon T cell receptor activation. In this study, a member of the tumour necrosis factor receptor (TNFR)-family, CD137 (4-1BB) was investigated for its potential to identify the total pool of circulating alloreactive T cells. Optimal conditions for sensitive and specific detection of allogeneic-induced CD137 expression on circulating T cells were established. Thereafter, CD137+ alloreactive T cells were phenotypically and functionally characterized by multi-parameter flow cytometry. Alloantigen-induced CD137 expression identified both alloreactive CD8 + T cells (mean ± standard error of the mean: 0·21 ± 0·07%) and alloreactive CD4 + T cells (0·21 ± 0·05%). CD137 + alloreactive T cells were detected in different T cell subsets, including naive T cells, but were found preferentially in CD28+ T cells and not in the terminally differentiated T cell subset. Upon allogeneic (re-)stimulation, the cytokine-producing as well as proliferative capacity of T cells resided mainly within the CD137-expressing fraction. About 10% of the CD137 + alloreactive T cells produced any combination of interferon (IFN)-γ, interleukin (IL)-2 and TNF-α. Polyfunctional alloreactive T cells, defined by multiple cytokine expression, were observed infrequently. In conclusion, activation-induced CD137 expression is a fast assay allowing for detection and functional analysis of the total alloreactive T cell compartment at the single-cell level by multiparameter flow cytometry.

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Critical Role of Regulatory T Cells in Th17-Mediated Minor Antigen-Disparate Rejection

Abstract: Material

Cited by 57 publications

References 53 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

IL-17 Deficiency Attenuates Allograft Injury and Prolongs Survival in a Murine Model of Fully MHC-Mismatched Renal Allograft Transplantation

Activation-induced CD137 is a fast assay for identification and multi-parameter flow cytometric analysis of alloreactive T cells

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