Regulatory T cells differentially modulate the maturation and apoptosis of human CD8+ T-cell subsets

Nikolova, Maria; Lelièvre, Jean‐Daniel; Carrière, Matthieu; Bensussan, Armand; Lévy, Yves

doi:10.1182/blood-2008-04-151407

Cited by 63 publications

(61 citation statements)

References 56 publications

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“…43 A significantly increased expression of CD39 on Tregs from HIV-1-infected patients was described previously in a study suggesting that the CD39-adenosine axis could be involved in Treg-mediated inhibition in these patients. 44 The fact that treatment with an anti-CD39 blocking antibody reduced the capacity of Tregs to decrease HIV infection in Tcons strongly supports the hypothesis that cAMP induction in Tcons plays an important role in Treg control of HIV infection.…”

Section: Pka Activation Plays a Significant Role In Treg-mediated Supmentioning

confidence: 48%

Regulatory T cells control HIV replication in activated T cells through a cAMP-dependent mechanism

Moreno‐Fernandez

Rueda

Rusie

et al. 2011

Blood

111

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We hypothesized that regulatory T cells (Tregs) could play a beneficial role during HIV infection by controlling HIV replication in conventional T cells (Tcons). Purified Tregs and Tcons from healthy donors were activated separately. Tcons were infected with the X4 or R5 HIV strains and cultured with or without autologous Tregs. Coculture of Tcons and Tregs resulted in a dose-dependent inhibition of Tcon infection, which was significant when a 1:1 Treg:Tcon ratio was used. Treg suppression of HIV infection was largely mediated by contact-dependent mechanisms. Blockage of cytotoxic T-lymphocyte–associated antigen-4 did not significantly reduce Treg function. In contrast, Tregs acted through cAMP-dependent mechanisms, because the decrease of cAMP levels in Tregs, the blockade of gap junction formation between Tregs and Tcons, the blockage of CD39 activity, and the blockage of protein kinase A in Tcons all abolished Treg-mediated suppression of HIV replication. Our data suggest a complex role for Tregs during HIV infection. Although Tregs inhibit specific immune responses, their inhibition of HIV replication in Tcons may play a beneficial role, particularly during early HIV infection, when the effector immune cells are not yet activated. Such a protective role of Tregs could have a profound impact on infection outcome.

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Section: Pka Activation Plays a Significant Role In Treg-mediated Supmentioning

confidence: 48%

Regulatory T cells control HIV replication in activated T cells through a cAMP-dependent mechanism

Moreno‐Fernandez

Rueda

Rusie

et al. 2011

Blood

111

View full text Add to dashboard Cite

show abstract

“…Indeed, revelations from intravital microscopy indicate that regulatory T cells are far more frequently in contact with DCs than with T effector cells [124,125] and our growing understanding of the suppressive function of regulatory T cells that are induced through interaction with DCs both support this notion [126]. Adding yet another level of intricacy to the dynamic interplay between DCs, effector and regulatory T cells, recent evidence suggests regulatory T cells may differentially modulate memory responses and have the potential to affect anti-tumor immunity in an unexpected fashion [127].…”

Section: Inflammatory Mediators In the Tumor Microenvironment Initiatmentioning

confidence: 86%

Dendritic cells integrate signals from the tumor microenvironment to modulate immunity and tumor growth

et al. 2010

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“…Selective suppression of CD8 T-cell effector function by natural Tregs has been previously reported in Friend retrovirus infection and anti-CD3-activated responses. CD4 ϩ CD25 ϩ T cells were found to directly suppress IFN-␥ production and effector CD8 T-cell expansion by inhibiting differentiation of CD8 T cells from memory to effector but had limited effect on IL-2 production (31,36). In our study, the M 209 -immunized mice have fewer RSV-specific CD8 T cells in peripheral lymphoid organs, and those present have relatively high CD127 expression, which is a phenotypic marker associated with memory differentiation.…”

Section: Discussionmentioning

confidence: 73%

“…Violet fluorescent reactive dye and anti-CD19-and anti-CD16/32-Pacific Blue from Invitrogen were used as cell viability and lineage markers to exclude dead and non-T cells from analysis (33). Peptide [26][27][28][29][30][31][32][33][34][35][36][37][38][39] -PE, were prepared by NIH Tetramer Facility (Atlanta, GA). Staining protocols were described previously (27,39).…”

Section: Methodsmentioning

confidence: 99%

“…Detailed immunization and infection procedures were described previously (27). Mice were immunized with RSV M 209-223 or M2 [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39] peptide at 100 g/mouse intramuscularly. Peptides were conjugated with keyhole limpet hemocyanin (KLH) by using an Imject immunogen EDC kit (Thermo Fisher Scientific, Inc., Illinois).…”

Section: Methodsmentioning

confidence: 99%

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Epitope-Specific Regulatory CD4 T Cells Reduce Virus-Induced Illness while Preserving CD8 T-Cell Effector Function at the Site of Infection

Liu

Ruckwardt

Chen

et al. 2010

J Virol

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The role of epitope-specific regulatory CD4 T cells in modulating CD8 T-cell-mediated immunopathology during acute viral infection has not been well defined. In the murine model of respiratory syncytial virus (RSV) infection, CD8 T cells play an important role in both viral clearance and immunopathology. We have previously characterized two RSV epitope-specific CD4 T-cell responses with distinct phenotypic properties. One of them, the IA b M 209 -specific subset, constitutively expresses FoxP3 and modulates CD8 T-cell function in vitro. We show here that the IA b M 209 -specific CD4 T-cell response regulates CD8 T-cell function in vivo and is associated with diminished RSV-induced illness without affecting viral clearance at the site of infection. Achieving the optimal balance of regulatory and effector T-cell function is an important consideration for designing future vaccines.A subset of CD4 T cells with regulatory function (Treg) has been shown to play an important role in modulating adaptive immune responses. Natural Tregs are characterized by the expression of FoxP3 and participate in reducing the activation of CD8 T-cell responses in peripheral lymphoid organs (11, 20,35). This modulation can diminish the ability of adaptive immune responses to control systemic infections (4). However, the presence of natural regulatory CD4 T cells can have a beneficial effect on immune-mediated pathology, particularly at the site of infection. Tregs have been shown to limit pulmonary inflammation and lung injury induced by pneumocystis infection (29) and to modulate herpes simplex virus-induced inflammatory lesions of the eye (46). Natural Tregs also reduce the symptoms of West Nile virus infections in both humans and mice; Treg-deficient mice were more likely to develop lethal infection (25). Viral infection can also induce antigen-specific CD4 T cells that express FoxP3 (27), and their role in protective immunity and immunopathology needs more detailed investigation.T lymphocytes are key components of adaptive immunity against respiratory syncytial virus (RSV) infection. Children with T-cell deficiencies have delayed virus clearance and are more susceptible to fatal RSV infection (10, 18). The absence of T cells infiltrating into lung is associated with fatal RSV infections in children without recognized underlying disease (49). In the murine model, CD8 T cells play a major role in RSV clearance, presumably through direct cytotoxicity to infected cells and the generation of immunocompetent molecules (2, 15, 43); depletion of CD8 T cells in mice results in delayed viral clearance (14). The CD8 T-cell response also induces immunopathology in primary infection of mice (15,32,48). Transferring high doses of CD8 T cells facilitates virus clearance but also causes hemorrhagic pneumonia and enhanced disease (6, 14). These studies demonstrate that while CD8 T cells are required for viral clearance, they are responsible for immunopathology. We have described the pattern of CD8 T-cell responses that occur in mice that are the F 1...

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Regulatory T cells differentially modulate the maturation and apoptosis of human CD8+ T-cell subsets

Cited by 63 publications

References 56 publications

Regulatory T cells control HIV replication in activated T cells through a cAMP-dependent mechanism

Regulatory T cells control HIV replication in activated T cells through a cAMP-dependent mechanism

Dendritic cells integrate signals from the tumor microenvironment to modulate immunity and tumor growth

Epitope-Specific Regulatory CD4 T Cells Reduce Virus-Induced Illness while Preserving CD8 T-Cell Effector Function at the Site of Infection

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