Regulatory T Cells Suppress Antiviral Immune Responses and Increase Viral Loads during Acute Infection with a Lymphotropic Retrovirus

Zelinskyy, Gennadiy; Dietze, Kirsten K.; Sparwasser, Tim; Dittmer, Ulf

doi:10.1371/journal.ppat.1000406

Cited by 65 publications

(80 citation statements)

References 16 publications

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“…These virus-induced Tregs can actively suppress the antiviral effector functions of FV-specific CD8 + T cells, as has been shown by adoptive transfer experiments using T-cell receptor (TCR) transgenic (Tg) CD8 + T cells that recognize an immunodominant FV epitope (15). At 6-8 wk post-FV infection, the mice were injected with DT, which resulted in 98% depletion of GFP + Tregs at 1 wk postdepletion, a similar depletion efficacy as in naive mice or mice acutely infected with FV (5,8). After Treg depletion, a more than twofold increase in the mean frequency of activated (CD43 + ) CD8 + T cells was detected in the lymph nodes and spleen (Fig.…”

Section: Resultsmentioning

confidence: 81%

“…Injection of DT into these animals specifically eliminates Foxp3-expressing Tregs, although leaving the overall composition of other lymphocyte subsets intact (8,9). Foxp3-negative Tregs, which have been found in mice (10,11), cannot be depleted in this model.…”

Section: Cytotoxic T Cells | Retrovirus | Friend Virusmentioning

confidence: 92%

“…Intracellular granzyme B (monoclonal anti-human granzyme B antibody allophycocyanin (APC)-conjugated, clone GB12; Caltag Laboratories) staining was performed as described (14). Intracellular staining for IFN-γ, TNF-α, and IL-2 was performed as described (8). Foxp3 expression was detected by intracellular staining using the anti-mouse/rat Foxp3 antibody (clone FJK-16s) and the Foxp3 staining set (eBioscience).…”

Section: Methodsmentioning

confidence: 99%

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Transient depletion of regulatory T cells in transgenic mice reactivates virus-specific CD8 ⁺ T cells and reduces chronic retroviral set points

Dietze

Zelinskyy

Gibbert

et al. 2011

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

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115

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Although chronic infections with viruses such as HIV and hepatitis C virus have been associated with regulatory T cell (Treg)-mediated suppression of virus-specific CD8 + T-cell activity, no causal relationship between Tregs and chronic viral set points has been established. Using transgenic mice in which Tregs can be selectively ablated, we now show that transient depletion of Tregs during a chronic retroviral infection allows exhausted CD8 + T cells to regain antiviral functions, including secretion of cytokines, production of cytotoxic molecules, and virus-specific cytolytic activity. Furthermore, short-term Treg ablation resulted in long-term reductions in chronic virus loads. These results demonstrate that Tregmediated immunosuppression can be a significant factor in the maintenance of chronic viral infections and that Treg-targeted immunotherapy could be a valuable component in therapeutic strategies to treat chronic infectious diseases.cytotoxic T cells | retrovirus | friend virus

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Section: Resultsmentioning

confidence: 81%

Section: Cytotoxic T Cells | Retrovirus | Friend Virusmentioning

confidence: 92%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Transient depletion of regulatory T cells in transgenic mice reactivates virus-specific CD8 ⁺ T cells and reduces chronic retroviral set points

Dietze

Zelinskyy

Gibbert

et al. 2011

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

Self Cite

115

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“…That Treg cells play a critical role in the control of autoimmunity is illustrated by the fact that loss-of-function mutations in the FoxP3 gene, as well as depletion of Treg cells (12, 13), result in fatal autoimmune disease in humans and mice (14-17). Furthermore, naturally occurring FoxP3 + Treg cells were shown to regulate inflammatory disorders such as colitis and immune responses to transplants, tumors, vaccines, and infectious agents (6,18,19).To investigate the role of FoxP3 + Treg cells in peripheral tolerance of CD8 + T cells, we crossed DIETER mice to DEREG mice, thus generating a system in which FoxP3 + Treg cells can be depleted by injection of diphtheria toxin (DT) (13) and in which peripheral tolerance results from induced antigen presentation by steady-state DC (3). We found that the induction of peripheral tolerance by steady-state DC was severely impaired in the absence of regulatory T cells.…”

mentioning

confidence: 99%

mentioning

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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