IL-17A–Producing γδT Cells Promote CTL Responses against <i>Listeria monocytogenes</i> Infection by Enhancing Dendritic Cell Cross-Presentation

Xu, Sheng; Yun, Han; Xu, Xiongfei; Bao, Yan; Zhang, Minggang; Cao, Xuetao

doi:10.4049/jimmunol.1001763

Cited by 78 publications

(71 citation statements)

References 56 publications

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“…Both CD4 ϩ Th17 cells and ␥␦-T cells, the major cells that produce IL-17A, have been previously shown to promote CD8 ϩ T cell cytotoxicity during infection (101,102) and autoimmune disease (103) and in cancers (104,105). Also, NK cells treated with IL-17A upregulate the expression of perforin and granzyme genes and cytotoxic functions (106), which provides additional evidence that IL-17A signaling can induce the expression of cytotoxicity mediators.…”

Section: Discussionmentioning

confidence: 71%

Interleukin-17A Promotes CD8⁺T Cell Cytotoxicity To Facilitate West Nile Virus Clearance

Acharya

Wang

Paul

et al. 2017

J Virol

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CD8 ϩ T cells are crucial components of immunity and play a vital role in recovery from West Nile virus (WNV) infection. Here, we identify a previously unrecognized function of interleukin-17A (IL-17A) in inducing cytotoxic-mediator gene expression and promoting CD8 ϩ T cell cytotoxicity against WNV infection in mice. We find that IL-17A-deficient (Il17a Ϫ/Ϫ ) mice are more susceptible to WNV infection and develop a higher viral burden than wild-type (WT) mice. Interestingly, the CD8 ϩ T cells isolated from Il17a Ϫ/Ϫ mice are less cytotoxic and express lower levels of cytotoxic-mediator genes, which can be restored by supplying recombinant IL-17A in vitro and in vivo. Importantly, treatment of WNV-infected mice with recombinant IL-17A, as late as day 6 postinfection, significantly reduces the viral burden and increases survival, suggesting a therapeutic potential for IL-17A. In conclusion, we report a novel function of IL-17A in promoting CD8 ϩ T cell cytotoxicity, which may have broad implications in other microbial infections and cancers.IMPORTANCE Interleukin-17A (IL-17A) and CD8 ϩ T cells regulate diverse immune functions in microbial infections, malignancies, and autoimmune diseases. IL-17A is a proinflammatory cytokine produced by diverse cell types, while CD8 ϩ T cells (known as cytotoxic T cells) are major cells that provide immunity against intracellular pathogens. Previous studies have demonstrated a crucial role of CD8 ϩ T cells in recovery from West Nile virus (WNV) infection. However, the role of IL-17A during WNV infection remains unclear. Here, we demonstrate that IL-17A protects mice from lethal WNV infection by promoting CD8 ϩ T cell-mediated clearance of WNV. In addition, treatment of WNV-infected mice with recombinant IL-17A reduces the viral burden and increases survival of mice, suggesting a potential therapeutic. This novel IL-17A-CD8 ϩ T cell axis may also have broad implications for immunity to other microbial infections and cancers, where CD8 ϩ T cell functions are crucial.

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Section: Discussionmentioning

confidence: 71%

Interleukin-17A Promotes CD8⁺T Cell Cytotoxicity To Facilitate West Nile Virus Clearance

Acharya

Wang

Paul

et al. 2017

J Virol

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“…2C). Because IL-12p70 is well known to augment CTL activation (10,11,33), these results demonstrate that CD11b negatively regulates CpG-ODN-induced IL-12p70 production in DCs and, in turn, impairs DC cross-priming of the CTL response. …”

Section: Cd11b Represses DC Cross-priming Of Ctl Response By Inhibitimentioning

confidence: 86%

“…In vitro and in vivo Ag-specific CD8 T cell proliferation was measured, as described previously (33). BMDCs from CD11b-deficient or wild-type mice were purified using CD11c magnetic microbeads, pretreated or not with anti-IL-12p70 (10 mg/ml), stimulated with LPS (100 ng/ml) or CpG-ODN (0.3 mM) for 1 d, pulsed with OVA protein (20 mg/ml), and then cocultured with naive OT-I T cells (purified using CD8 magnetic microbeads from OT-I mice) at a ratio of 1:10 for 2 d. Cells were double stained with anti-CD8-FITC and 7-aminoactinomycin D, resuspended in exactly 300 ml PBS, and acquired for 56 s at high speed using a flow cytometer.…”

Section: Analysis Of Ag Cross-presentationmentioning

confidence: 99%

Integrin CD11b Negatively Regulates TLR9-Triggered Dendritic Cell Cross-Priming by Upregulating microRNA-146a

Bai

Qian

et al. 2012

The Journal of Immunology

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Dendritic cells (DCs) play critical roles in cross-priming to induce the CTL response against infection; however, the molecular mechanisms for the regulation of DC cross-priming need to be investigated further, which may help to improve the potency of DC vaccines through engineering modifications. Our previous studies showed that β2 integrin CD11b could control TLR-triggered NK cell cytotoxicity and macrophage inflammatory responses. CD11b is also abundantly expressed in DCs, but it is unknown whether CD11b participates in the regulation of DC cross-priming for the CTL response. Also, because microRNAs (miRNAs) are important regulators of the immune response, it remains unclear whether miRNAs are regulated by CD11b in DCs. In this study, we showed that CD11b deficiency upregulated TLR9-triggered, but not TLR4-triggered, IL-12p70 production in DCs, subsequently promoting DC cross-priming of the CTL response. Further experiments showed that CD11b selectively promoted TLR9-triggered miR-146a upregulation in DCs by sustaining late-phase NF-κB activation. Additionally, Notch1, a known positive regulator of IL-12p70 production in DCs, was confirmed to be directly targeted by miR-146a. miR-146a upregulation and Notch1 repression were determined to be responsible for the reduced IL-12p70 production in TLR9-triggered wild-type DCs compared with that in CD11b-deficient DCs. Therefore, CD11b and downstream miR-146a may be new negative regulators for DC cross-priming by suppressing Notch1 expression and IL-12p70 production. Our data indicate a new mechanism for the regulation of DC cross-priming through integrins and miRNAs.

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“…In some experiments, neutralizing anti-FasL mAb or anti-CD11c mAb were included in the coculture system. The cytotoxicity of CD8 T cell subsets against EG7 target cells or activated CD4 T cells was measured using flow cytometry as previously described (32,33). Cells were collected, stained with 7-aminoactinomycin D and analyzed by FACS LSRII.…”

Section: Cd11cmentioning

confidence: 99%

CD11chighCD8+ Regulatory T Cell Feedback Inhibits CD4 T Cell Immune Response via Fas Ligand–Fas Pathway

Chen

Yun

et al. 2013

The Journal of Immunology

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Regulatory T cells can restrict the uncontrolled immune response and inflammation, avoiding pathologic immune injury to the host and thus playing important roles in the maintenance of immune homeostasis. Until recently, many subsets of CD4 and CD8 regulatory T cells have been reported. In this study, we identified CD11chighCD8+ T cells as a new subset of CD8+ regulatory T cells. During Listeria monocytogenes and Staphylococcus aureus infection, two subsets of CD8 T cells were classified according to the expression level of CD11c, including CD11clowCD8+ and CD11chighCD8+ T cells. CD11clowCD8+ T cells, existing during the whole period of infection, act as conventional activated T cells to kill target cells in a perforin-dependent manner. Interestingly, CD11chighCD8+ T cells appeared only at a late stage of infection, expressed relatively high CD122 and low CD69, did not secrete IFN-γ, IL-10, TGF-β, and exhibited much more potent cytotoxicity against target cells via Fas ligand–Fas pathway in an Ag-independent manner. Ligation of CD11c was important in the cytotoxicity of CD11chighCD8+ T cells. Furthermore, CD11chighCD8+ T cells could directly kill the activated CD4 T cells both in vitro and in vivo, whereas CD11clowCD8+ T cells could not. Thus, we identified an infection-induced new subset of CD11chighCD8+ regulatory T cells, which might contribute to protect host from pathological immune injure. Our results indicate that CD11c+CD8+ T cells are constitute a heterogeneous population that can be divided further into regulatory CD11chighCD8+ T cell subset and effector CD11clowCD8+ T cell subset, thus adding insight to the role of CD8 T cells in immune response and regulation.

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IL-17A–Producing γδT Cells Promote CTL Responses against Listeria monocytogenes Infection by Enhancing Dendritic Cell Cross-Presentation

Cited by 78 publications

References 56 publications

Interleukin-17A Promotes CD8⁺T Cell Cytotoxicity To Facilitate West Nile Virus Clearance

Interleukin-17A Promotes CD8⁺T Cell Cytotoxicity To Facilitate West Nile Virus Clearance

Integrin CD11b Negatively Regulates TLR9-Triggered Dendritic Cell Cross-Priming by Upregulating microRNA-146a

CD11chighCD8+ Regulatory T Cell Feedback Inhibits CD4 T Cell Immune Response via Fas Ligand–Fas Pathway

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IL-17A–Producing γδT Cells Promote CTL Responses against Listeria monocytogenes Infection by Enhancing Dendritic Cell Cross-Presentation

Cited by 78 publications

References 56 publications

Interleukin-17A Promotes CD8+T Cell Cytotoxicity To Facilitate West Nile Virus Clearance

Interleukin-17A Promotes CD8+T Cell Cytotoxicity To Facilitate West Nile Virus Clearance

Integrin CD11b Negatively Regulates TLR9-Triggered Dendritic Cell Cross-Priming by Upregulating microRNA-146a

CD11chighCD8+ Regulatory T Cell Feedback Inhibits CD4 T Cell Immune Response via Fas Ligand–Fas Pathway

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Interleukin-17A Promotes CD8⁺T Cell Cytotoxicity To Facilitate West Nile Virus Clearance

Interleukin-17A Promotes CD8⁺T Cell Cytotoxicity To Facilitate West Nile Virus Clearance