Natural killer T cells contribute to the control of acute retroviral infection
© The Author(s) 2017
Received: 25 July 2016
Accepted: 3 January 2017
Published: 26 January 2017
Natural killer T cells (NKT cells) play an important role in the immunity against viral infections. They produce cytokines or have direct cytolytic effects that can restrict virus replication. However, the exact function of NKT cells in retroviral immunity is not fully elucidated. Therefore, we analyzed the antiretroviral functions of NKT cells in mice infected with the Friend retrovirus (FV).
After FV infection numbers of NKT cells remained unchanged but activation as well as improved effector functions of NKT cells were found. While the release of pro-inflammatory cytokines was not changed after infection, activated NKT cells revealed an elevated cytotoxic potential. Stimulation with α-Galactosylceramide significantly increased not only total NKT cell numbers and activation but also the anti-retroviral capacity of NKT cells.
We demonstrate a strong activation and a potent cytolytic function of NKT cells during acute retroviral infection. Therapeutic treatment with α-Galactosylceramide could further improve the reduction of early retroviral replication by NKT cells, which could be utilized for future treatment against viral infections.
Natural killer T cells (NKT cells) are innate-like T lymphocytes, which recognize glycolipid antigens presented by the non-classical major histocompatibility complex (MHC) class I-like molecule CD1d. NKT cells express markers, which are associated with the T cell (αβ T cell receptor) as well as the NK cell (e.g. NK cell activating C-type lectin NK1.1) lineage. They can be divided into type I (invariant or classical) and type II (non-classical) NKT cell subsets dependent on the expression of the invariant Vα14-Jα18 gene segment in mice or Vα24-Jα18 receptor in humans . Activation of NKT cells occur in the absence of prior foreign antigen priming [2, 3]. For their activation several pathways are feasible such as direct stimulation via CD1d-presented lipids and/or in combination with the cytokines Interleukin (IL)-12, IL-18 as well as type I interferons (IFNs) or only cytokine-mediated activation without T cell receptor signaling . NKT cells reveal important immunoregulatory functions by massive release of T helper (Th) 1 or Th2 cytokines. Thus, NKT cells activate and recruit several other cell types including NK cells, T cells, B cells, dendritic cells and neutrophils [5, 6]. In addition, they can kill infected or transformed cells through Fas-FasL mediated apoptosis and/or the perforin/granzyme exocytosis pathway [7, 8]. Engagement of the death receptor Fas by FasL results in apoptosis mediated by caspase activation .
NKT cells are essential for the containment of bacterial, parasites, fungal pathogens, cancer, and also viral infections. The importance of NKT cells during viral infections becomes clear given that several viruses like Lymphocytic Choriomeningitis Virus (LCMV), Cytomegalovirus (CMV), vesicular stomatitis virus, vaccinia virus, Herpes Simplex Virus (HSV)-1 and Human Immunodeficiency Virus (HIV)-1 disrupt CD1d expression on infected target cells to evade antiviral effects of NKT cells [10–13]. In those studies, mainly IFNγ production by NKT cells was analyzed. However, the exact role of NKT cells during retroviral infection is not known so far.
The Friend virus (FV) mouse model can be utilized to analyze and therapeutically modulate the function of NKT cells during acute retroviral infection in vivo. We and others have previously shown that NK cells play an important role in innate FV immunity [14–16], but NKT cells were not studied so far. FV inoculation into mice leads to infection of erythroid precursor cells as well as granulocytes and B cells . FV consists of two components: the spleen focus forming virus (SFFV) and the Friend murine leukemia virus (F-MuLV). SFFV represents the pathogenic but replication-defective part of the viral complex whereas F-MuLV is replication-competent but apathogenic . Infection of C57BL/6 mice results only in mild splenomegaly, but high dose infection facilitates establishment of a chronic infection. In FV-infected mice, the highest viral loads are found in the bone marrow and spleen, so we analyzed these two organs after acute FV infection . Here, we demonstrate the activation and anti-retroviral efficacy of NKT cells during acute FV infection. Furthermore, we elucidated the potential role of NKT cells for immunotherapy of retrovirus infections.
NKT cells became activated during initial FV infection
Although we could not detect differences in total NKT cell numbers, we detected a more activated phenotype of NKT cells in FV-infected mice.
Cytokine production by NKT cells during initial FV infection
Thus, acute FV infection seems to induce the production of anti-inflammatory but not pro-inflammatory cytokines in NKT cells.
Acute FV infection enhanced the cytotoxic potential of NKT cells
The data demonstrates that acute FV infection enhances the ability of NKT cells to kill FV-transformed target cells.
Cytokine production and cytotoxicity of NKT cell sub-populations during early FV infection
Cytokine production and cytotoxicity of NKT cell sub-populations during early FV infection
17 ± 6
12 ± 9
70 ± 9
24 ± 5
7 ± 6
67 ± 10
29 ± 8
13 ± 7
51 ± 19
35 ± 7
11 ± 8
46 ± 15
46 ± 6
11 ± 10
37 ± 6
64 ± 9
3 ± 3
26 ± 8
50 ± 9
2 ± 1
37 ± 7
65 ± 10
3 ± 3
27 ± 11
24 ± 4
6 ± 5
64 ± 11
23 ± 11
11 ± 6
58 ± 17
8 ± 6
12 ± 7
76 ± 8
13 ± 12
20 ± 12
55 ± 15
These results suggest different functions of NKT cell sub-populations, with CD4+ NKT cells mainly producing anti-inflammatory cytokines, whereas DN NKT cells express molecules associated with cytotoxicity.
Antiviral effect of NKT cells in vivo and therapeutic stimulation of NKT cells during FV infection
Stimulation with αGalCer also led to NK cell (CD3−CD49b+NK1.1+) activation and cytokine production. We therefore analyzed the expression of CD69 on NK cells and their production of pro-inflammatory cytokines in FV-infected mice after αGalCer administration (Additional file 2: Figure S2 D). We detected an activation of NK cells post FV infection, which was significantly enhanced post αGalCer therapy (Additional file 2: Figure S2 D, CD69, black bars). The αGalCer treatment also increased the percentages of TNFα produced by NK cells (Additional file 2: Figure S2 D, gray bars). IFNγ production by NK cells was induced by FV infection, but was not further enhanced post αGalCer administration (Additional file 2: Figure S2 D, white bars). Thus, secondary effects of NKT cell stimulation on NK cells may partly contribute to the anti-retroviral effects after αGalCer therapy.
In this report, we analyzed the impact of NKT cells on the control of viral replication during initial phase of acute FV infection (3 dpi). We could demonstrate cytotoxicity of activated NKT cells and anti-retroviral activity in vivo. Most importantly, antiviral functions of NKT cells could be further increased by glycolipid αGalCer therapy that resulted in approximately 90% reduction in viral loads.
Various functions of NKT cells were also described in other viral infections. For example, increased numbers of NKT cells were detected in the lungs of influenza A virus (IAV) infected mice and the survival rate of NKT knockout mice after IAV infection was reduced [27, 28]. In these studies, the activation of NKT cells correlated with the reduction of IAV replication and reduced weight loss of mice . Furthermore, NKT cells decreased immunopathology during IAV infection by reducing the accumulation of inflammatory monocytes in the lung . In HIV infection NKT cell responses are difficult to analyze because functions of NKT cells are impaired and HIV infection results in loss of NKT cells within the first year of infection [30–32]. The initiation of antiretroviral therapy (ART) in HIV-infected individuals results in a slow recovery of circulating NKT cell subsets and improves their functionality [31, 32]. Recently it was shown that NKT cells can directly recognize and respond specifically to HIV-1-infected DCs . In this study, NKT cell sensing of HIV-infected cells depends on the expression of the CD1d molecule and the presentation of endogenous lipid antigen, which is at least partially downregulated by the accessory proteins Nef and Vpu . HIV is closely related to SIV that causes AIDS in macaques and serves as a well-accepted primate model for HIV infection . A study in SIV-infected macaques that develop AIDS versus SIV-infected sooty mangabeys that are disease resistant, revealed a hypofunction of NKT cells in SIV-infected macaques . The authors concluded that NKT dysfunction may play a role in AIDS pathogenesis and that immunoregulatory NKT cells might prevent generalized immune activation and immunodeficiency . During acute FV infection, NKT cells showed direct cytotoxic activity, but no increased production of pro-inflammatory cytokines. Thus, the antiviral effect of these cells in FV-infected mice was most likely mediated by direct target cell killing and not by cytokine-induced activation of other effector cells. If the enhanced production of anti-inflammatory cytokines by NKT cells after FV infection counter-regulates immunopathology, as reported for the IAV model and SIV-infected AIDS-resistant sooty mangabeys, remains to be investigated in future studies.
Diverse immunoregulatory functions of NKT cells can be classified by phenotypic differences based on their CD4 and CD8 expression or by the absence of both molecules (DN) [1, 5]. In humans, CD4− NKT cells reveal a rather cytolytic function and a Th1-biased cytokine profile while CD4+ NKT cells produce high levels of Th2 and also Th1-associated cytokines and exhibit immunoregulatory functions [36, 37]. During HIV and SIV infection, the CD4+ NKT cell subset was depleted, which was inversely correlated with viral loads [21, 22, 38] whereas others did not detect any correlations between NKT cell depletion and viral set points [30, 39]. During FV infection we did not detect a depletion of CD4+ NKT cells probably due to the fact that FV mainly infects erythroid precursor cells as well as granulocytes and B cells . Similar to other studies we found that CD4+ NKT mainly produced Th2 cytokines, whereas the DN NKT cell subset expressed markers associated with immune activation and cytotoxicity. Therefore, the anti-retroviral activity of NKT cells during FV infection is most likely mediated by the DN NKT cell sub-population.
Immunotherapies targeting NKT cells as effectors aim at increasing NKT cell numbers or enhancing their effector functions. For the stimulation of NKT cells in SIV-infected macaques the exact protocol is of crucial importance for the proper initiation of NKT cell responses . Treatment protocols from mouse experiments were not successful for the activation of NKT cells in humans and macaques . Recently it was demonstrated that the administration of αGalCer to macaques infected with SIV resulted in an initial transient decline of NKT cell frequencies followed by an NKT cell expansion at six to nine days post αGalCer therapy . Nevertheless, αGalCer was able to efficiently activate NKT cells in SIV-infected macaques . In acutely FV-infected mice, the activation of NKT cells with αGalCer was associated with increased NKT cell numbers in the bone marrow and slightly in the spleen, better activation, and improved antiviral responses of NKT cells. Stimulation of FV-infected animals with αGalCer resulted in a significantly increased FasL expression on NKT cells, which was not seen in naïve mice stimulated with αGalCer. Therefore, αGalCer treatment might be an interesting new immunotherapy against retroviral infections. Interestingly, αGalCer was also tested as a mucosal adjuvant against genital herpes . Here, immunization with HSV-2 glycoprotein D in combination with αGalCer improved the IgG antibody response and resulted in complete protection against vaginal HSV-2 challenge . In Hepatitis B virus (HBV) infection, NKT cells were shown to be initially activated and contribute to the antiviral immune response by promoting adaptive immune responses . Independently of T and B cells, stimulation of NKT cells with αGalCer abolished viral replication and increased concentrations of IFNγ and type I IFNs in HBV-transgenic mice were detected . However, type I IFN responses do not play a critical role in the FV model because they are actively suppressed by the virus [45, 46]. In hepatitis virus infections NKT cells also seem to have opposing effects on pathogenesis. Beside the positive effects of activated hepatic NKT cells in preventing acute liver injury, inflammation and fibrosis, other studies demonstrated that NKT cells may also contribute to hepatic injuries in an FasL-dependent damage of hepatocytes [47, 48]. Furthermore, the excessive activation of NKT cells can result in accelerated liver damage [48, 49]. Thus, activation of hepatic NKT cells was not only associated with beneficial effects but also with impaired liver regeneration in HBV-transgenic mice . In the FV model, αGalCer therapy had a beneficial effect on the course of infection, but important aspects of immunopathology have to be carefully considered for every pathogen when augmenting NKT cell responses.
In this report, we describe the impact of NKT cells on the control of an acute retroviral infection. Stimulation of NKT cells with αGalCer improved their anti-retroviral potential, which might be an interesting new approach for immunotherapy of acute virus infections.
Mice and FV infection
Seven to ten weeks old female inbred C57BL/6 (B6, Harlan Laboratories, Germany) were used for the experiments. All mice were treated in accordance with the regulations and guidelines of the institutional animal care and use committee of University of Duisburg-Essen. The FV stock used in these experiments was FV complex containing B-tropic Friend murine leukemia helper virus and polycythemia-inducing spleen focus-forming virus. The stock was prepared as a 15% spleen cell homogenate from BALB/c mice infected 14 days previously with 3000 spleen focus-forming units (SFFU). Mice were injected intravenously with 0.1 ml phosphate-buffered saline containing 40,000 SFFU of FV. The virus stock did not contain lactate dehydrogenase-elevating virus. Mice were sacrificed 3 dpi by cervical dislocation and spleen and bone marrow (two legs) were harvested.
Infectious centers (IC) were detected by tenfold dilutions of single-cell suspensions of splenocytes and bone marrow cells onto Mus dunnis cells. Co-cultures were incubated for three days, fixed with ethanol, stained with F-MuLV envelope-specific monoclonal antibody 720 and developed with peroxidase-conjugated goat anti-mouse antibody and aminoethylcarbazol for the detection of foci.
Cell surface staining was performed for 15 min in the dark using PBS. The exclusion of dead cells was achieved using Zombie UV dye (BioLegend). Cells were stimulated with Ionomycin (500 ng/ml), PMA (25 ng/ml), Monesin (1×, BioLegend) and Brefeldin A (2 μg/ml) diluted in IMDM buffer and incubated for 3 h at 37 °C to detect cytokines and FasL expression. For intracellular stainings BD Cytofix/Cytoperm Fixation/Permeabilization kit was used. Surface and intracellular stainings were performed using following antibodies: CD3 (17A2, eBioscience), CD43 (1B11, BioLegend), CD49b (Dx5, eBioscience), CD69 (H1.2F3, eBioscience) CD86 (GL1, BioLegend), CD107a (ID4B, BioLegend), FasL (MFL3, BD Pharmingen), IFNγ (XMG1.2, eBioscience), IL-10 (JES5-16E3, eBioscience) IL-13 (eBio13A, eBioscience), NK1.1 (PK136, eBioscience), and TNFα (MP6-XT22, BioLegend).
In vitro cytotoxicity assay
FBL-3 tumor cells were cultured in RPMI plus 1% Penicillin/Streptomycin and 10% FBS. In vitro cytotoxicity assay was performed using 1 × 104 CFSE stained FBL-3 tumor cells and 25 × 104 isolated NKT cells from the spleen and the bone marrow of naive or FV-infected mice. The assay was performed in 96-well U-bottom plates and co-incubation took place for 24 h in a humidified 5% CO2 atmosphere at 37 °C. Cells were washed once, stained for fixable viability dye (FVD, eBioscience) to exclude dead cells and analyzed by flow cytometry.
NKT cell stimulation and isolation
At day 0 of FV infection, NKT cells were stimulated by i. p. application of 2 µg chemically synthesized αGalCer (KRN7000, Cayman Chemical Company) diluted in PBS. For isolation of NKT cells, CD3+ cells were isolated with MagniSort® Mouse CD3 Positive Selection Kit (eBioscience) and cells were sorted for NK1.1+ cells. For transfer experiment, 1 × 105 NKT cells per mouse were diluted in PBS and injected i.v. at the day of FV infection.
Statistical analyses and graphical presentations were computed with Graph Pad Prism version 6. Statistical differences between two different groups were determined by the Mann–Whitney test. Differences between three groups were analyzed by Kruskal–Wallis test. Outliers were identified with the Rout method.
ELS designed and performed the experiments, analyzed the data, participated in the statistical analysis and wrote the paper. SS performed several experiments. UD designed the experiments and wrote the paper. All authors read and approved the final manuscript.
This work was supported by a Grant from the University of Duisburg-Essen (IFORES). We thank the Imaging Center Essen (IMCES) for their services.
The authors declare that they have no competing interests.
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