Effective expansion of alloantigen-specific Foxp3+CD25+CD4+regulatory T cells by dendritic cells during the mixed leukocyte reaction

Yamazaki, Sayuri; Patel, Malini; Harper, Alice; Bonito, Anthony J.; Fukuyama, Hidehiro; Pack, Maggi; Tarbell, Kristin V.; Talmor, Mia; Ravetch, Jeffrey V.; Inaba, Kayo; Steinman, Ralph M.

doi:10.1073/pnas.0510606103

Cited by 173 publications

(172 citation statements)

References 33 publications

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“…Recent studies have identified different subsets of DCs that have different abilities to activate Th and Tregs and can induce either immunity or tolerance (47)(48)(49)(50)(51). By targeting the MUC1 Ag to the appropriate population of DCs, one might be able to dictate the nature and outcome of the DC-T cell interaction to favor the induction of Th cells over Tregs, thereby promoting the establishment of effective tumor-specific memory CTLs.…”

Section: Discussionmentioning

confidence: 99%

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Lack of Effective MUC1 Tumor Antigen-Specific Immunity in MUC1-Transgenic Mice Results from a Th/T Regulatory Cell Imbalance That Can Be Corrected by Adoptive Transfer of Wild-Type Th Cells

Turner

Cohen

Finn

2007

The Journal of Immunology

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Glycoprotein tumor Ag MUC1 is overexpressed on the majority of epithelial adenocarcinomas. CTLs that recognize MUC1 and can kill tumor cells that express this molecule have been found in cancer patients, yet they are present in low frequency and unable to eradicate MUC1+ tumors. Patients also make anti-MUC1 Abs but predominantly of the IgM isotype reflecting the lack of effective MUC1-specific Th responses. Mice transgenic for the human MUC1 gene (MUC1-Tg) are similarly hyporesponsive to MUC1. We used a vaccine consisting of dendritic cells loaded with a long synthetic MUC1 peptide to investigate the fate and function of MUC1-specific CD4+ Th elicited in wild-type (WT) or MUC1-Tg mice or adoptively transferred from vaccinated WT mice. We show that hyporesponsiveness of MUC1-Tg mice to this vaccine is a result of insufficient expansion of Th cells, while at the same time their regulatory T cells are efficiently expanded to the same extent as in WT mice and exert a profound suppression on MUC1-specific B and T cell responses in vivo. Adoptive transfer of WT Th cells relieved this suppression and enhanced T and B cell responses to subsequent MUC1 immunization. Our data suggest that the balance between Th and regulatory T cells is a critical parameter that could be modulated to improve the response to cancer vaccines.

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Section: Discussionmentioning

confidence: 99%

“…D, Specific lysis of the MUC1 ϩ tumor RMA-MUC1. Pooled LN cells were incubated for 4 h with 51 Cr-labeled RMA or RMA-MUC1 targets in triplicate.…”

Section: Dc-muc1 Vaccine Elicits Muc1-specific Tregs That Limit the Fmentioning

confidence: 99%

Lack of Effective MUC1 Tumor Antigen-Specific Immunity in MUC1-Transgenic Mice Results from a Th/T Regulatory Cell Imbalance That Can Be Corrected by Adoptive Transfer of Wild-Type Th Cells

Turner

Cohen

Finn

2007

The Journal of Immunology

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“…DC can differentiate T regs in the thymus [78] and in the periphery [79], and expand them once the T regs have formed [80][81][82]. Antigen-specific T regs are much more effective than polyclonal populations in suppressing immunity in vivo [79,[81][82][83]. For many years, the major approach to the induction of peripheral tolerance has been to inject very large doses of antigen.…”

Section: Tolerogenicity Another Side Of Immunogenicitymentioning

confidence: 99%

Dendritic cells: Understanding immunogenicity

2007

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The impetus for the discovery of dendritic cells in 1972 was to understand immunogenicity, the capacity of an antigenic substance to provoke immunity. During experiments to characterize "accessory" cells that enhanced immunity, we spotted unusual stellate cells in mouse spleen. They had a distinct capacity to form and retract processes or dendrites and were named dendritic cells (DC). DC proved to be different from other cell types and to be peculiarly immunogenic when loaded with antigens. When Langerhans cells were studied, immunogenicity was found to involve two steps: antigen presentation by immature DC and maturation to elicit immunity. Antigenbearing DC were also immunogenic in vivo and were therefore termed "nature's adjuvants". Several labs then learned to generate large numbers of DC from progenitors, which accelerated DC research. Tolerogenicity via DC, including the control of foxp3 + suppressor T cells, was recently discovered. Two areas of current research that I find intriguing are to identify mechanisms for antigen uptake and processing, and for the control of different types of immunity and tolerance. These subjects should be studied in vivo with clinically relevant antigens, so that the activities of DC can be better integrated into the prevention and treatment of disease in patients.

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“…Therefore, polyspecific CD4 + CD25 high cells are currently being evaluated after stem cell transplantation [13]. However, under nonlymphopenic conditions as seen in patients with autoimmune diseases or in patients after organ transplantation, polyspecific Treg cells have so far been largely ineffective in controlling immune responses [5,14,15] [24], and CD137 (4-1BB) [25] were described as Treg-cell activation markers after polyspecific Treg-cell activation.In this manuscript, we demonstrated for the first time that LAP and GARP can be used for the isolation of highly pure alloantigenspecific Treg cells. In addition, we showed that CD40 ligand (CD154) is not expressed on naïve and activated Treg cells.…”

mentioning

confidence: 99%

Isolation of human antigen‐specific regulatory T cells with high suppressive function

et al. 2014

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Adoptive transfer of regulatory T (Treg) cells could be an alternative to chronic immunosuppression for prevention of allogeneic graft rejection. While polyspecific Treg cells can prevent immune responses under lymphopenic conditions, Ag-specific Treg cells are needed to treat autoimmunity and graft rejection. Yet, reliable markers for Ag-specific Treg cells are missing. We report that latency-associated peptide (LAP) and glycoprotein A repetitions predominant (GARP) can identify human Ag-specific Treg cells. In addition,we show that the depletion of CD154 + cells from LAP + or GARP + Treg cells increases the Treg-cell purity to over 90%, as assessed by epigenetic analysis. These Ag-specific Treg cells can be isolated magnetically and might contribute to the development of GMP-based protocols. In addition, Ag-specific Treg cells are functionally far superior to CD4 + CD25 high or CD4 + CD25 high CD127 low Treg cells in vitro and in preventing strong alloreactions in humanized mice. They could, therefore, have a high therapeutic potential for the control of alloimmune, autoimmune, and allergic immune responses in patients.Keywords: Antigen-specific r CD154 r GARP r LAP r Regulatory T (Treg) cells Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionIn organ transplantation, acute rejection can be prevented by a combination of nonspecific immunosuppressive drugs and immunomodulatory induction therapies, yet chronic rejection and chronic graft dysfunction remain a clinical problem [1]. In addition, chronic nonspecific immunosuppression causes renal dysfunction and predisposes patients to infections and increased Correspondence: Dr. Elmar Jaeckel e-mail: Jaeckel.Elmar@mh-hannover.de risk of malignancies [1]. Innate and adaptive immune responses can be controlled by Treg cells, thereby offering new therapeutic options after organ transplantation [2][3][4][5][6]. CD4 + CD25 high FOXP3 + Treg cells have been shown to be of major importance in allospecific tolerance in animal models and to influence donor-specific immune responses in transplant patients [7][8][9][10]. After allogeneic hematopoietic stem cell transplantation, polyspecific Treg cells can prevent GVH disease without influencing * These authors contributed equally to this work.C 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2014. 44: 2592-2602 Cellular immune response 2593 graft-versus-leukemia responses [11,12]. Therefore, polyspecific CD4 + CD25 high cells are currently being evaluated after stem cell transplantation [13]. However, under nonlymphopenic conditions as seen in patients with autoimmune diseases or in patients after organ transplantation, polyspecific Treg cells have so far been largely ineffective in controlling immune responses [5,14,15] [24], and CD137 (4-1BB) [25] were described as Treg-cell activation markers after polyspecific Treg-cell activation.In this manuscript, we demonstrated for the first time that LAP and GARP can be use...

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Effective expansion of alloantigen-specific Foxp3⁺CD25⁺CD4⁺regulatory T cells by dendritic cells during the mixed leukocyte reaction

Cited by 173 publications

References 33 publications

Lack of Effective MUC1 Tumor Antigen-Specific Immunity in MUC1-Transgenic Mice Results from a Th/T Regulatory Cell Imbalance That Can Be Corrected by Adoptive Transfer of Wild-Type Th Cells

Lack of Effective MUC1 Tumor Antigen-Specific Immunity in MUC1-Transgenic Mice Results from a Th/T Regulatory Cell Imbalance That Can Be Corrected by Adoptive Transfer of Wild-Type Th Cells

Dendritic cells: Understanding immunogenicity

Isolation of human antigen‐specific regulatory T cells with high suppressive function

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