Browsing by Author "Lynette Beattie"

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Blimp-1-Dependent IL-10 Production by Tr1 Cells Regulates TNF-Mediated Tissue Pathology
(Public Library of Science, 2016) Marcela Montes de Oca; Rajiv Kumar; Fabian de Labastida Rivera; Fiona H Amante; Meru Sheel; Rebecca J. Faleiro; Patrick T. Bunn; Shannon E. Best; Lynette Beattie; Susanna S. Ng; Chelsea L. Edwards; Werner Muller; Erika Cretney; Stephen L. Nutt; Mark J. Smyth; Ashraful Haque; Geoffrey R. Hill; Shyam Sundar; Axel Kallies; Christian R. Engwerda
Tumor necrosis factor (TNF) is critical for controlling many intracellular infections, but can also contribute to inflammation. It can promote the destruction of important cell populations and trigger dramatic tissue remodeling following establishment of chronic disease. Therefore, a better understanding of TNF regulation is needed to allow pathogen control without causing or exacerbating disease. IL-10 is an important regulatory cytokine with broad activities, including the suppression of inflammation. IL-10 is produced by different immune cells; however, its regulation and function appears to be cell-specific and context-dependent. Recently, IL-10 produced by Th1 (Tr1) cells was shown to protect host tissues from inflammation induced following infection. Here, we identify a novel pathway of TNF regulation by IL-10 from Tr1 cells during parasitic infection. We report elevated Blimp-1 mRNA levels in CD4+ T cells from visceral leishmaniasis (VL) patients, and demonstrate IL-12 was essential for Blimp-1 expression and Tr1 cell development in experimental VL. Critically, we show Blimp-1-dependent IL-10 production by Tr1 cells prevents tissue damage caused by IFNγ-dependent TNF production. Therefore, we identify Blimp-1-dependent IL-10 produced by Tr1 cells as a key regulator of TNF-mediated pathology and identify Tr1 cells as potential therapeutic tools to control inflammation. © 2016 Montes de Oca et al.
Combined Immune Therapy for the Treatment of Visceral Leishmaniasis
(Public Library of Science, 2016) Rebecca J. Faleiro; Rajiv Kumar; Patrick T. Bunn; Neetu Singh; Shashi Bhushan Chauhan; Meru Sheel; Fiona H. Amante; Marcela Montes de Oca; Chelsea L. Edwards; Susanna S. Ng; Shannon E. Best; Ashraful Haque; Lynette Beattie; Louise M. Hafner; David Sacks; Susanne Nylen; Shyam Sundar; Christian R. Engwerda
Chronic disease caused by infections, cancer or autoimmunity can result in profound immune suppression. Immunoregulatory networks are established to prevent tissue damage caused by inflammation. Although these immune checkpoints preserve tissue function, they allow pathogens and tumors to persist, and even expand. Immune checkpoint blockade has recently been successfully employed to treat cancer. This strategy modulates immunoregulatory mechanisms to allow host immune cells to kill or control tumors. However, the utility of this approach for controlling established infections has not been extensively investigated. Here, we examined the potential of modulating glucocorticoid-induced TNF receptor-related protein (GITR) on T cells to improve anti-parasitic immunity in blood and spleen tissue from visceral leishmaniasis (VL) patients infected with Leishmania donovani. We found little effect on parasite growth or parasite-specific IFNγ production. However, this treatment reversed the improved anti-parasitic immunity achieved by IL-10 signaling blockade. Further investigations using an experimental VL model caused by infection of C57BL/6 mice with L. donovani revealed that this negative effect was prominent in the liver, dependent on parasite burden and associated with an accumulation of Th1 cells expressing high levels of KLRG-1. Nevertheless, combined anti-IL-10 and anti-GITR mAb treatment could improve anti-parasitic immunity when used with sub-optimal doses of anti-parasitic drug. However, additional studies with VL patient samples indicated that targeting GITR had no overall benefit over IL-10 signaling blockade alone at improving anti-parasitic immune responses, even with drug treatment cover. These findings identify several important factors that influence the effectiveness of immune modulation, including parasite burden, target tissue and the use of anti-parasitic drug. Critically, these results also highlight potential negative effects of combining different immune modulation strategies. © 2016 Almeida et al.
Rapid loss of group 1 innate lymphoid cells during blood stage Plasmodium infection
(Wiley-Blackwell, 2018) Susanna S Ng; Fernando Souza-Fonseca-Guimaraes; Fabian De Labastida Rivera; Fiona H Amante; Rajiv Kumar; Yulong Gao; Meru Sheel; Lynette Beattie; Marcela Montes De Oca; Camille Guillerey; Chelsea L Edwards; Rebecca J Faleiro; Teija Frame; Patrick T Bunn; Eric Vivier; Dale I Godfrey; Daniel G Pellicci; J Alejandro Lopez; Katherine T Andrews; Nicholas D Huntington; Mark J Smyth; James McCarthy; Christian R Engwerda
Objectives: Innate lymphoid cells (ILCs) share many characteristics with CD4+ T cells, and group 1 ILCs share a requirement for T-bet and the ability to produce IFNγ with T helper 1 (Th1) cells. Given this similarity, and the importance of Th1 cells for protection against intracellular protozoan parasites, we aimed to characterise the role of group 1 ILCs during Plasmodium infection. Methods: We quantified group 1 ILCs in peripheral blood collected from subjects infected with with Plasmodium falciparum 3D7 as part of a controlled human malaria infection study, and in the liver and spleens of PcAS-infected mice. We used genetically-modified mouse models, as well as cell-depletion methods in mice to characterise the role of group 1 ILCs during PcAS infection. Results: In a controlled human malaria infection study, we found that the frequencies of circulating ILC1s and NK cells decreased as infection progressed but recovered after volunteers were treated with antiparasitic drug. A similar observation was made for liver and splenic ILC1s in P. chabaudi chabaudi AS (PcAS)-infected mice. The decrease in mouse liver ILC1 frequencies was associated with increased apoptosis. We also identified a population of cells within the liver and spleen that expressed both ILC1 and NK cell markers, indicative of plasticity between these two cell lineages. Studies using genetic and cell-depletion approaches indicated that group 1 ILCs have a limited role in antiparasitic immunity during PcAS infection in mice. Discussion: Our results are consistent with a previous study indicating a limited role for natural killer (NK) cells during Plasmodium chabaudi infection in mice. Additionally, a recent study reported the redundancy of ILCs in humans with competent B and T cells. Nonetheless, our results do not rule out a role for group 1 ILCs in human malaria in endemic settings given that blood stage infection was initiated intravenously in our experimental models, and thus bypassed the liver stage of infection, which may influence the immune response during the blood stage. Conclusion: Our results show that ILC1s are lost early during mouse and human malaria, and this observation may help to explain the limited role for these cells in controlling blood stage infection. In a controlled human malaria infection study, we found that the frequencies of circulating ILC1s and NK cells decreased as infection progressed, but recovered after volunteers were treated with antiparasitic drug. A similar observation was made for liver and splenic ILC1s in P. chabaudi chabaudi AS (PcAS)-infected mice. Studies using genetic and cell-depletion approaches indicated that group 1 ILCs have a limited role in antiparasitic immunity during PcAS infection in mice. © 2018 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australasian Society for Immunology Inc.
Type I Interferons Regulate Immune Responses in Humans with Blood-Stage Plasmodium falciparum Infection
(Elsevier B.V., 2016) Marcela Montes de Oca; Rajiv Kumar; Fabian de Labastida Rivera; Fiona H. Amante; Meru Sheel; Rebecca J. Faleiro; Patrick T. Bunn; Shannon E. Best; Lynette Beattie; Susanna S. Ng; Chelsea L. Edwards; Glen M. Boyle; Ric N. Price; Nicholas M. Anstey; Jessica R. Loughland; Julie Burel; Denise L. Doolan; Ashraful Haque; James S. McCarthy; Christian R. Engwerda
The development of immunoregulatory networks is important to prevent disease. However, these same networks allow pathogens to persist and reduce vaccine efficacy. Here, we identify type I interferons (IFNs) as important regulators in developing anti-parasitic immunity in healthy volunteers infected for the first time with Plasmodium falciparum. Type I IFNs suppressed innate immune cell function and parasitic-specific CD4+ T cell IFNγ production, and they promoted the development of parasitic-specific IL-10-producing Th1 (Tr1) cells. Type I IFN-dependent, parasite-specific IL-10 production was also observed in P. falciparum malaria patients in the field following chemoprophylaxis. Parasite-induced IL-10 suppressed inflammatory cytokine production, and IL-10 levels after drug treatment were positively associated with parasite burdens before anti-parasitic drug administration. These findings have important implications for understanding the development of host immune responses following blood-stage P. falciparum infection, and they identify type I IFNs and related signaling pathways as potential targets for therapies or vaccine efficacy improvement. © 2016 The Author(s)