Foxp3<sup>+</sup>natural regulatory T cells preferentially form aggregates on dendritic cells<i>in vitro</i>and actively inhibit their maturation

Onishi, Yasushi; Fehérvari, Zoltán; Yamaguchi, Tomoyuki; Sakaguchi, Shimon

doi:10.1073/pnas.0711106105

Cited by 602 publications

(552 citation statements)

References 39 publications

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“…A decreased CTLA-4 expression level was previously described in activated cells [21,22], and it is known that CTLA-4 is essential for initial Treg in vivo suppressor activity on APCs [23,24]. According to our results, we suggest that rapid CTLA-4 internalization occurs in Tregs at the moment of contact with APCs, suppressing the expression of MHC II and/or B7 molecules on the later.…”

Section: Discussionsupporting

confidence: 81%

Early skin immunological disturbance after Plasmodium-infected mosquito bites

Silva

Caetano

Monteiro

et al. 2012

Cellular Immunology

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a b s t r a c tAlthough the role of regulatory T cells (Tregs) during malaria infection has been studied extensively, such studies have focused exclusively on the role of Treg during the blood stage of infection; little is known about the detailed mechanisms of Tregs and sporozoite deposition in the dermis by mosquito bites. In this paper we show that sporozoites introduced into the skin by mosquito bites increase the mobility of skin Tregs and dendritic cells (DCs). We also show differences in MHC class II and/or CD86 expression on skin-resident dendritic cell subtypes and macrophages. From the observed decrease of the number of APCs into draining lymph nodes, suppression of CD28 expression in conventional CD4 T cells, and a low homeostatic proliferation of skin-migrated CD4 T found in nude mice indicate that Tregs may play a fundamental role during the initial phase of malaria parasite inoculation into the mammalian host.

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Section: Discussionsupporting

confidence: 81%

Early skin immunological disturbance after Plasmodium-infected mosquito bites

Silva

Caetano

Monteiro

et al. 2012

Cellular Immunology

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“…BMDCs express higher levels of costimulatory molecules than splenic DCs, even before activation, and the ability of Treg cells to control maturation of the former was a matter of debate [7]. Several studies showed that DCs activated with LPS were refractory to Treg-cell regulation [26,27].…”

Section: Discussionmentioning

confidence: 99%

Cell‐extrinsic CTLA4‐mediated regulation of dendritic cell maturation depends on STAT3

2014

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Regulatory T (Treg) cells suppress immune responses by downregulating the expression of costimulatory molecules CD80 and CD86 on dendritic cells (DCs) through cytotoxic T lymphocyte antigen 4 (CTLA4). However, it is unclear whether inducible Treg (iTreg) cellscan hamper immune responses via the same mechanism. Moreover, whether a reverse signal sent by CTLA4 alone is sufficient to prevent maturation of DCs has never been evaluated. Here, we demonstrate that stimulation of DCs with CTLA4, either expressed by inducible Treg cells or by cross-linking with CTLA4Fc fusion protein, can significantly inhibit LPS-induced CD80 and CD86 mRNA and protein expression in both mouse and human DCs. Importantly, CTLA4Fc-treated DCs had reduced ability to stimulate CD4 + and CD8 + T-cell proliferation and cytokine production in both syngeneic and allogeneic settings. We also investigated the molecular mechanism involved in the induction of tolerogenic DCs by CTLA4. We determined that the interaction of CTLA4 with its high affinity ligand CD80 on DCs induces STAT3 phosphorylation followed by reduction of NF-κB activity, leading to suppression of CD80 and CD86 gene transcription and protein production. Our work opens new windows for the generation of tolerogenic DCs that could ultimately be used for treating autoimmune diseases and transplant rejection. Keywords: Dendritic cells r Immune regulation r Regulatory T cells r ToleranceAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionDendritic cells (DCs) play a central role in the initiation and regulation of immune responses [1]. Although traditionally viewed as immunity inducers, in the absence of inflammatory danger signals, DCs participate in the maintenance of peripheral tolerance [2] and can induce T-cell deletion, anergy and generation and expansion of regulatory T (Treg) cells [3]. These tolerogenic DCs show decreased expression of costimulatory molecules such as CD80Correspondence: Dr. Li Zhang e-mail: lzhang@uhnres.utoronto.ca and CD86 and reduced production of proinflammatory cytokines [4]. Several in vitro methods have been developed in order to generate tolerogenic DCs [5]. Additionally, a growing body of experimental data highlights the role of Treg cells in maintaining tolerance through the suppression of DC immunostimulatory capacity [6][7][8][9]. However, the molecular mechanisms by which Treg cells modulate DC function remain obscure. Elucidation of the mechanisms governing DC maturation may facilitate their use in treating a variety of immune-related conditions including autoimmune diseases and transplantation.CD4 + CD25 + Foxp3 + Treg cells play a pivotal role in maintaining self-tolerance and preventing autoimmunity. At least two major subtypes of CD4 + CD25 + Foxp3 + Treg cells have been identified: Thymus-derived natural T regulatory (nTreg) cells and C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu1144 Aleksandra Kowalczyk et al. Eur. J. Immunol. 2014. 44: 1143-1155 ...

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“…Overall, these results show that direct contact-based interactions between T reg and T eff cells persisted with or without CD11c + DCs, which could reflect distinct subsets of T cells or distinct stages of the T cell function in the target tissues. The functional relevance of the different types of interactions has already been documented in vitro (Takahashi et al, 1998;Thornton and Shevach, 1998;Ermann et al, 2001;Nakamura et al, 2001;Piccirillo and Shevach, 2001;BaecherAllan et al, 2006;Tadokoro et al, 2006;Onishi et al, 2008;Wing et al, 2008;Hagness et al, 2012;Huang et al, 2012). Our noninvasive in vivo imaging studies shows that those The data were pooled from 6 videos from three experiments with 5 mice.…”

Section: T Reg Cells Persistently Interacted With T Eff Cells Even Whmentioning

confidence: 96%

“…Two groups independently reported that T reg cells could not suppress in vitro proliferation responses of T eff cells if they were placed in a different chamber in a trans-well culture system (Takahashi et al, 1998;Thornton and Shevach, 1998). Although this could be attributed to an effect of T reg cells on antigen-presenting cells (Tadokoro et al, 2006;Onishi et al, 2008;Wing et al, 2008), robust evidence has also been presented antigen-specificity, as opposed to bystander killing (Tite and Janeway, 1984), shapes tissue fate in the effector phase.…”

Section: Sem) (E)mentioning

confidence: 99%

Real-time immune cell interactions in target tissue during autoimmune-induced damage and graft tolerance

Jason¹,

Abdulreda²,

Devarajan³

et al. 2014

J Cell Biol

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Real-time imaging studies are reshaping immunological paradigms, but a visual framework is lacking for self-antigen-specific T cells at the effector phase in target tissues. To address this issue, we conducted intravital, longitudinal imaging analyses of cellular behavior in nonlymphoid target tissues to illustrate some key aspects of T cell biology. We used mouse models of T cell-mediated damage and protection of pancreatic islet grafts. Both CD4 + and CD8 + effector T (T eff ) lymphocytes directly engaged target cells. Strikingly, juxtaposed  cells lacking specific antigens were not subject to bystander destruction but grew substantially in days, likely by replication. In target tissue, Foxp3 + regulatory T (T reg ) cells persistently contacted T eff cells with or without involvement of CD11c + dendritic cells, an observation conciliating with the in vitro "trademark" of T reg function, contact-dependent suppression. This study illustrates tolerance induction by contact-based immune cell interaction in target tissues and highlights potentials of tissue regeneration under antigenic incognito in inflammatory settings.

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Foxp3⁺natural regulatory T cells preferentially form aggregates on dendritic cellsin vitroand actively inhibit their maturation

Cited by 602 publications

References 39 publications

Early skin immunological disturbance after Plasmodium-infected mosquito bites

Early skin immunological disturbance after Plasmodium-infected mosquito bites

Cell‐extrinsic CTLA4‐mediated regulation of dendritic cell maturation depends on STAT3

Real-time immune cell interactions in target tissue during autoimmune-induced damage and graft tolerance

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Foxp3+natural regulatory T cells preferentially form aggregates on dendritic cellsin vitroand actively inhibit their maturation

Cited by 602 publications

References 39 publications

Early skin immunological disturbance after Plasmodium-infected mosquito bites

Early skin immunological disturbance after Plasmodium-infected mosquito bites

Cell‐extrinsic CTLA4‐mediated regulation of dendritic cell maturation depends on STAT3

Real-time immune cell interactions in target tissue during autoimmune-induced damage and graft tolerance

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Foxp3⁺natural regulatory T cells preferentially form aggregates on dendritic cellsin vitroand actively inhibit their maturation