CD4+ regulatory T cells require CTLA-4 for the maintenance of systemic tolerance

Friedline, Randall H.; Brown, David Spaulding; Nguyen, Hai Vu; Kornfeld, Hardy; Lee, Jin‐Hee; Zhang, Yi; Appleby, Mark W.; Der, Sandy D.; Kang, Joonsoo; Chambers, Cynthia A.

doi:10.1084/jem.20081811

Cited by 237 publications

(179 citation statements)

References 71 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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“…However, the response in the absence of Treg cells is comparable in magnitude to the response observed when only CTLA-4 interactions were blocked. This is of particular interest in the light of experiments demonstrating a crucial role of CTLA-4 in the suppressive function of Treg cells (22)(23)(24)(25). (20,27), up-regulate IL-10 (28) and the coinhibitory molecule B7-H3, and are compromised in the stimulation of naive T cells (27).…”

Section: Discussionmentioning

confidence: 99%

FoxP3 ⁺ regulatory T cells essentially contribute to peripheral CD8 ⁺ T-cell tolerance induced by steady-state dendritic cells

Schildknecht

Brauer

Brenner

et al. 2010

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

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Peripheral T-cell tolerance is thought to significantly contribute to the prevention of autoimmunity, and it has been shown that antigenpresenting steady-state dendritic cells efficiently induce peripheral tolerance. We previously showed that dendritic-cell-induced tolerance is a T-cell-intrinsic process that depends on coinhibitory molecules such as programmed death-1. Here we specifically analyze the involvement of FoxP3 + regulatory T cells, which are known to be important for maintenance of self-tolerance. We show that antigen presentation by steady-state dendritic cells failed to induce peripheral tolerance in the absence of FoxP3 + regulatory T cells but induced protective CD8 + T-cell-mediated immunity instead. Regulatory T-cell-depleted mice had massively increased numbers of dendritic cells in lymph nodes. Dendritic cells isolated from mice without regulatory T cells had upregulated costimulatory molecules and showed stronger T-cell stimulatory capacity ex vivo, suggesting that regulatory T cells contribute to peripheral tolerance by keeping the dendritic cells in an immature state. Using blocking antibodies, we demonstrate that CTLA-4 but not IL-10 is necessary for control of dendritic cells by regulatory T cells.M ost autoreactive T cells are deleted in the thymus by socalled "negative selection." Although this process is efficient, the presence of autoreactive T cells in every healthy individual demonstrates that it is not complete (1). Peripheral, mature autoreactive T cells are kept in check by peripheral tolerance, which acts through a variety of mechanisms that are not necessarily mutually exclusive and that include unresponsiveness/ anergy, regulation/suppression, and deletion.We and others have recently demonstrated that dendritic cells (DCs) play a central role in the induction of peripheral tolerance (2-4). Using transgenic mice that allow the inducible expression of viral cytotoxic T lymphocyte (CTL) epitopes selectively by DCs (DIETER mice), we showed that presentation of CTL epitopes by steady-state DCs induces robust tolerance in antigen-specific CD8 + T cells. We found that this tolerance depends on signaling via the inhibitory receptors programmed death-1 (PD-1) and cytotoxic T lymphocyte antigen 4 (CTLA-4) and follows a recessive mechanism such as induction of anergy in, or deletion of, CD8 + T cells specific for the antigens presented by the steady-state DCs. Using adoptive transfer of naive T cells into tolerant mice, we did not find any evidence for involvement of a dominant suppressive mechanism such as the induction of antigen-specific regulatory T cells (Treg cells) or the production of immunosuppressive cytokines. We did not, however, formally address the contribution of Treg cells to peripheral tolerance induced by steady-state DCs in DIETER mice (3, 4). CD4 + CD25 + FoxP3 + Treg cells, first characterized by their immunosuppressive properties (5, 6), comprise ≈10-15% of all peripheral CD4 + T cells in mice. The forkhead box transcription factor FoxP3 is the best marker for Tre...

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“…These results confirmed that the Ctex/Cd3z locus controls CTLA-4 expression in CD4 + and CD8 + T cells and restricted the region of interest to 28.8 Mb. CTLA-4 plays an important role in the function of CD4 + CD25 + Foxp3 + regulatory T cells (28)(29)(30); therefore, we specifically analyzed the expression of CTLA-4 in this subset. A significantly lower frequency of Foxp3 + T cells expressed CTLA-4 in NOD compared with B6 mice (Fig.…”

Section: Defective Expression Of Cd3z and Ctla-4 In Nod T Cells Aftermentioning

confidence: 99%

Variation in the Cd3ζ (Cd247) Gene Correlates with Altered T Cell Activation and Is Associated with Autoimmune Diabetes

Lundholm

Mayans

Motta

et al. 2010

The Journal of Immunology

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CD4+ regulatory T cells require CTLA-4 for the maintenance of systemic tolerance

Cited by 237 publications

References 71 publications

Early skin immunological disturbance after Plasmodium-infected mosquito bites

Early skin immunological disturbance after Plasmodium-infected mosquito bites

FoxP3 ⁺ regulatory T cells essentially contribute to peripheral CD8 ⁺ T-cell tolerance induced by steady-state dendritic cells

Variation in the Cd3ζ (Cd247) Gene Correlates with Altered T Cell Activation and Is Associated with Autoimmune Diabetes

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CD4+ regulatory T cells require CTLA-4 for the maintenance of systemic tolerance

Cited by 237 publications

References 71 publications

Early skin immunological disturbance after Plasmodium-infected mosquito bites

Early skin immunological disturbance after Plasmodium-infected mosquito bites

FoxP3 + regulatory T cells essentially contribute to peripheral CD8 + T-cell tolerance induced by steady-state dendritic cells

Variation in the Cd3ζ (Cd247) Gene Correlates with Altered T Cell Activation and Is Associated with Autoimmune Diabetes

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FoxP3 ⁺ regulatory T cells essentially contribute to peripheral CD8 ⁺ T-cell tolerance induced by steady-state dendritic cells