<i>Toxoplasma gondii</i> Inactivates Human Plasmacytoid Dendritic Cells by Functional Mimicry of IL-10

Pierog, Piotr; Zhao, Yanlin; Singh, Sukhwinder; Dai, Jihong; Yap, George; Fitzgerald-Bocarsly, Patricia

doi:10.4049/jimmunol.1701045

Cited by 22 publications

(24 citation statements)

References 38 publications

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“…It has been shown by our lab and others that pDC function can be altered by cytokines from neighboring cells [40,41,49]. TNFα and IL-10 have both been reported to inhibit IFNα production in pDCs, however the mechanism leading to this inhibition is unclear [41,49]. Indeed, when we pretreated with IL-10 there was diminished mean fluorescent intensity of IFNα after viral stimulation.…”

Section: Discussionmentioning

confidence: 85%

“…When we attempted to replicate our results from PBMCs in enriched pDC populations, we were unable to detect any alterations in E2-2 expression. It has been shown by our lab and others that pDC function can be altered by cytokines from neighboring cells [40,41,49]. TNFα and IL-10 have both been reported to inhibit IFNα production in pDCs, however the mechanism leading to this inhibition is unclear [41,49].…”

Section: Discussionmentioning

confidence: 95%

“…Although PBMCs are a very heterogenous population comprised of many immune cell populations, we investigated the potential role of monocytes in E2-2 regulation because monocytes have been implicated in the regulation of pDCs [40,41,49]. Depleting monocytes from PBMCs diminished the concentration of TNFα in the supernatants; however, there was still a low level of TNFα present.…”

Section: Discussionmentioning

confidence: 99%

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Regulation of Transcription Factor E2-2 in Human Plasmacytoid Dendritic Cells by Monocyte-Derived TNFα

Dewald

Fitzgerald-Bocarsly

2020

Viruses

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Plasmacytoid dendritic cells (pDCs) are innate immune cells and potent producers of interferon alpha (IFNα). Regulation of pDCs is crucial for prevention of aberrant IFN production. Transcription factor E2-2 (TCF4) regulates pDC development and function, but mechanisms of E2-2 control have not been investigated. We used freshly-isolated human peripheral blood mononuclear cells stimulated with toll-like receptor 7, 9, and 4 agonists to determine which factors regulate E2-2. After activation, pDCs decreased E2-2 expression. E2-2 downregulation occurred during the upregulation of costimulatory markers, after maximal IFN production. In congruence with previous reports in mice, we found that primary human pDCs that maintained high E2-2 levels produced more IFN, and had less expression of costimulatory markers. Stimulation of purified pDCs did not lead to E2-2 downregulation; therefore, we investigated if cytokine signaling regulates E2-2 expression. We found that tumor necrosis factor alpha (TNFα) produced by monocytes caused decreased E2-2 expression. All together, we established that primary human pDCs decrease E2-2 in response to TNFα and E2-2 low pDCs produce less IFN but exhibit more costimulatory molecules. Altered expression of E2-2 may represent a mechanism to attenuate IFN production and increase activation of the adaptive immune compartment.

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Section: Discussionmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

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Regulation of Transcription Factor E2-2 in Human Plasmacytoid Dendritic Cells by Monocyte-Derived TNFα

Dewald

Fitzgerald-Bocarsly

2020

Viruses

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“…Cytokine-induced memory-like NK cells can be generated in mice and humans after stimulation with IL-12, IL-18 and IL-15 (6, 28). All of these cytokines are produced during acute T. gondii infection (17, 42, 71, 72), with the exception of Type I IFNs (73). Therefore, it is surprising that NK cells do not further differentiate into memory-like cells.…”

Section: Discussionmentioning

confidence: 99%

The IL-12– and IL-23–Dependent NK-Cell Response is Essential for Protective Immunity Against SecondaryToxoplasma GondiiInfection

Ivanova

Mundhenke

Gigley

2019

Preprint

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22Natural Killer (NK) cells can develop memory-like features and contribute to long-term 23 immunity in mice and humans. NK cells are critical for protection against acute T. 24 gondii infection. However, whether they contribute to long-term immunity in response to this 25 parasite is unknown. We used a vaccine challenge model of parasite infection to address this 26 question and to define the mechanism by which NK cells are activated during secondary parasite 27 infection. We found NK cells were required for control of secondary infection. NK cells 28 increased in number at the infection site, became cytotoxic and produced IFNγ. Adoptive transfer 29 and NK-cell fate mapping revealed that T. gondii−experienced NK cells were not intrinsically 30 different from naïve NK cells with respect to their long-term persistence and ability to protect. 31 Thus, they did not develop memory-like characteristics. Instead, a cell-extrinsic mechanism may 32 control protective NK-cell responses during secondary infection. To test the involvement of a 33 cell-extrinsic mechanism, we used anti-IL-12p70 and IL-12p35 − / − mice and found that the 34 secondary NK-cell response was not fully dependent on IL-12. IL-23 depletion with anti-IL-35 23p19 in vivo significantly reduced the secondary NK-cell response, suggesting that both IL-12 36 and IL-23 were involved. Anti-IL-12p40 treatment, which blocks both IL-12 and IL-23, 37 eliminated the protective secondary NK-cell response, supporting this hypothesis. Our results 38 define a previously unknown protective role for NK cells during secondary T. gondii infection 39 that is dependent on IL-12 and IL-23. 40 to T. gondii. In the absence of CD4+ T cells, IFNγ produced by NK cells promotes CD8+ T-cell 65 activation (21). In the absence of CD8+ T cells, NK-cell IFNγ contributes to the activation of 66 CD4+ T cells (22). In addition to cytokine production, NK cells produce perforin and granzymes 67 in response to the parasite and its subcellular components (23)(24)(25)(26). 68 NK cells are clearly important for early control of T. gondii infection, yet their role in 69 long-term immunity has not been addressed. This is clinically important to understand because 70 there currently is no vaccine that elicits sterilizing immunity to the parasite (15, 27). A vaccine 71 targeting the stimulation of NK cells in addition to CD8+ T cells could therefore be more 72 beneficial long-term. In addition, T. gondii infection causes health complications in 73 immunodeficient patients, many of whom are T-cell deficient (e.g., HIV patients) (11). 74Discovering new ways to utilize NK cells could be therapeutically beneficial for these patients. 75In this study, we aimed to find whether NK cells contribute to long-term immunity 76 against T. gondii in a vaccine challenge setting. We also investigated whether NK cells 77 developed memory-like features in response to this vaccination. Lastly, we tested mechanisms 78 involved in the activation of NK cells during secondary challenge. We demonstrate that NK cells 79 a...

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“…The transcription factor IRF7 is essential for the induction of IFNα/β genes via the virus-activated, MyD88-independent pathway, and the TLR-activated, MyD88-dependent pathway (22). T. gondii infected human pDCs could functionally inhibit pDCs from producing IFNα responding to HIV-1 or HSV-1 during co-infection (23). The inhibition of IFNα production in response to HSV-1 infection has a dose-dependent effect on the ratio of T. gondii to human peripheral blood mononuclear cell counts, whereas uninfected cells responded normally to HSV-1 stimulation.…”

Section: The Roles Of Ifn-i In Co-infections With Toxoplasma Gondii Amentioning

confidence: 99%

The Roles of Type I Interferon in Co-infections With Parasites and Viruses, Bacteria, or Other Parasites

Lü

2020

Front. Immunol.

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Parasites, bacteria, and viruses pose serious threats to public health. Many parasite infections, including infections of protozoa and helminths, can inhibit inflammatory responses and impact disease outcomes caused by viral, bacterial, or other parasitic infections. Type I interferon (IFN-I) has been recognized as an essential immune effector in the host defense against various pathogens. In addition, IFN-I responses induced by co-infections with different pathogens may vary according to the host genetic background, immune status, and pathogen burden. However, there is only limited information on the roles of IFN-I in co-infections with parasites and viruses, bacteria, or other parasites. This review summarizes some recent findings on the roles of IFN-I in co-infections with parasites, including Leishmania spp., Plasmodium spp., Eimeria maxima, Heligmosomoides polygyrus, Brugia malayi, or Schistosoma mansoni, and viruses or bacteria and co-infections with different parasites (such as co-infection with Neospora caninum and Toxoplasma gondii, and co-infection with Plasmodium spp. and H. polygyrus). The potential mechanisms of host responses associated with co-infections, which may provide targets for immune intervention and therapies of the co-infections, are also discussed.

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Toxoplasma gondii Inactivates Human Plasmacytoid Dendritic Cells by Functional Mimicry of IL-10

Cited by 22 publications

References 38 publications

Regulation of Transcription Factor E2-2 in Human Plasmacytoid Dendritic Cells by Monocyte-Derived TNFα

Regulation of Transcription Factor E2-2 in Human Plasmacytoid Dendritic Cells by Monocyte-Derived TNFα

The IL-12– and IL-23–Dependent NK-Cell Response is Essential for Protective Immunity Against SecondaryToxoplasma GondiiInfection

The Roles of Type I Interferon in Co-infections With Parasites and Viruses, Bacteria, or Other Parasites

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