Browsing by Author "Chelsea L. Edwards"

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A molecular signature for IL-10–producing Th1 cells in protozoan parasitic diseases
(American Society for Clinical Investigation, 2023) Chelsea L. Edwards; Jessica A. Engel; Fabian de Labastida Rivera; Susanna S. Ng; Dillon Corvino; Marcela Montes de Oca; Teija C.M. Frame; Shashi Bhushan Chauhan; Siddharth Sankar Singh; Awnish Kumar; Yulin Wang; Jinrui Na; Pam Mukhopadhyay; Jason S. Lee; Susanne Nylen; Shyam Sundar; Rajiv Kumar; Christian R. Engwerda
Control of visceral leishmaniasis (VL) depends on proinflammatory Th1 cells that activate infected tissue macrophages to kill resident intracellular parasites. However, proinflammatory cytokines produced by Th1 cells can damage tissues and require tight regulation. Th1 cell IL-10 production is an important cell–autologous mechanism to prevent such damage. However, IL-10–producing Th1 (type 1 regulatory; Tr1) cells can also delay control of parasites and the generation of immunity following drug treatment or vaccination. To identify molecules to target in order to alter the balance between Th1 and Tr1 cells for improved antiparasitic immunity, we compared the molecular and phenotypic profiles of Th1 and Tr1 cells in experimental VL caused by Leishmania donovani infection of C57BL/6J mice. We also identified a shared Tr1 cell protozoan signature by comparing the transcriptional profiles of Tr1 cells from mice with experimental VL and malaria. We identified LAG3 as an important coinhibitory receptor in patients with VL and experimental VL, and we reveal tissue-specific heterogeneity of coinhibitory receptor expression by Tr1 cells. We also discovered a role for the transcription factor Pbx1 in suppressing CD4+ T cell cytokine production. This work provides insights into the development and function of CD4+ T cells during protozoan parasitic infections and identifies key immunoregulatory molecules. © 2023, Edwards et al.
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.
Correction to: The NK cell granule protein NKG7 regulates cytotoxic granule exocytosis and inflammation (Nature Immunology, (2020), 21, 10, (1205-1218), 10.1038/s41590-020-0758-6)
(Nature Research, 2024) Susanna S. Ng; Fabian De Labastida Rivera; Juming Yan; Dillon Corvino; Indrajit Das; Ping Zhang; Rachel Kuns; Shashi Bhushan Chauhan; Jiajie Hou; Xian-Yang Li; Teija C. M. Frame; Benjamin A. McEnroe; Eilish Moore; Jinrui Na; Jessica A. Engel; Megan S. F. Soon; Bhawana Singh; Andrew J. Kueh; Marco J. Herold; Marcela Montes de Oca; Siddharth Sankar Singh; Patrick T. Bunn; Amy Roman Aguilera; Mika Casey; Matthias Braun; Nazanin Ghazanfari; Shivangi Wani; Yulin Wang; Fiona H. Amante; Chelsea L. Edwards; Ashraful Haque; William C. Dougall; Om Prakash Singh; Alan G. Baxter; Michele W. L. Teng; Alex Loukas; Norelle L. Daly; Nicole Cloonan; Mariapia A. Degli-Esposti; Jude Uzonna; William R. Heath; Tobias Bald; Siok-Keen Tey; Kyohei Nakamura; Geoffrey R. Hill; Rajiv Kumar; Shyam Sundar; Mark J. Smyth; Christian R. Engwerda
Correction to: Nature Immunologyhttps://doi.org/10.1038/s41590-020-0758-6, published online 24 August 2020. The Chief Editor is correcting this article at the request of the corresponding author, Christian Engwerda. An investigation by QIMR Berghofer Medical Research Institute found that the original Figs. 7e, 7h (upper panel) and 8a and Extended Data Fig. 5b (EO771 data only) were based on experiments for which no evidence of their conduct or primary data could be confirmed. As such, the data from the underlying experiments are believed to have been fabricated or are unreliable, respectively. The four panels have been removed from Figs. 7 and 8 and Extended Data Fig. 5 (see Supplementary Information for a list of edits and original article for comparison). The major finding of the paper that NKG7 regulates cytotoxic granule exocytosis and inflammation remains unaffected. No concerns have been raised regarding other data in the paper. © The Author(s), under exclusive licence to Springer Nature America, Inc. 2024.
Distinct Roles for CD4+ Foxp3+ Regulatory T Cells and IL-10-Mediated Immunoregulatory Mechanisms during Experimental Visceral Leishmaniasis Caused by Leishmania donovani
(American Association of Immunologists, 2018) Patrick T. Bunn; Marcela Montes De Oca; Fabian De Labastida Rivera; Rajiv Kumar; Susanna S. Ng; Chelsea L. Edwards; Rebecca J. Faleiro; Meru Sheel; Fiona H. Amante; Teija C.M. Frame; Werner Muller; Ashraful Haque; Jude E. Uzonna; Geoffrey R. Hill; Christian R. Engwerda
The outcome of intracellular parasitic infection can be determined by the immunoregulatory activities of natural regulatory CD4+ Foxp3+ T (Treg) cells and the anti-inflammatory cytokine IL-10. These mechanisms protect tissue but can also suppress antiparasitic CD4+ T cell responses. The specific contribution of these regulatory pathways during human parasitic diseases remains unclear. In this study, we investigated the roles of Treg cells and IL-10 during experimental visceral leishmaniasis caused by Leishmania donovani infection of C57BL/6 mice. We report only a limited contribution of Treg cells in suppressing antiparasitic immunity, but important roles in delaying the development of splenic pathology and restricting leukocyte expansion. We next employed a range of cell-specific, IL-10- and IL-10R-deficient mice and found these Treg cell functions were independent of IL-10. Instead, conventional CD4+ T cells and dendritic cells were the most important cellular sources of IL-10, and the absence of IL-10 in either cell population resulted in greater control of parasite growth but also caused accelerated breakdown in splenic micro-architecture. We also found that T cells, dendritic cells, and other myeloid cells were the main IL-10-responding cells because in the absence of IL-10R expression by these cell populations, there was greater expansion of parasite-specific CD4+ T cell responses associated with improved control of parasite growth. Again, however, there was also an accelerated breakdown in splenic micro-architecture in these animals. Together, these findings identify distinct, cell-specific, immunoregulatory networks established during experimental visceral leishmaniasis that could be manipulated for clinical advantage. Copyright © 2018 by The American Association of Immunologists, Inc.
Galectin-1 impairs the generation of anti-parasitic Th1 cell responses in the liver during experimental visceral leishmaniasis
(Frontiers Media S.A., 2017) Patrick T. Bunn; Marcela Montes de Oca; Fabian de Labastida Rivera; Rajiv Kumar; Chelsea L. Edwards; Rebecca J. Faleiro; Susanna S. Ng; Meru Sheel; Yulin Wang; Fiona H. Amante; Ashraful Haque; Christian R. Engwerda
Many infectious diseases are characterized by the development of immunoregulatory pathways that contribute to pathogen persistence and associated disease symptoms. In diseases caused by intracellular parasites, such as visceral leishmaniasis (VL), various immune modulators have the capacity to negatively impact protective CD4+ T cell functions. Galectin-1 is widely expressed on immune cells and has previously been shown to suppress inflammatory responses and promote the development of CD4+ T cells with immunoregulatory characteristics. Here, we investigated the role of galectin-1 in experimental VL caused by infection of C57BL/6 mice with Leishmania donovani. Mice lacking galectin-1 expression exhibited enhanced tissue-specific control of parasite growth in the liver, associated with an augmented Th1 cell response. However, unlike reports in other experimental models, we found little role for galectin-1 in the generation of IL-10-producing Th1 (Tr1) cells, and instead report that galectin-1 suppressed hepatic Th1 cell development. Furthermore, we found relatively early effects of galectin-1 deficiency on parasite growth, suggesting involvement of innate immune cells. However, experiments investigating the impact of galectin-1 deficiency on dendritic cells indicated that they were not responsible for the phenotypes observed in galectin-1-deficient mice. Instead, studies examining galectin-1 expression by CD4+ T cells supported a T cell intrinsic role for galectin-1 in the suppression of hepatic Th1 cell development during experimental VL. Together, our findings provide new information on the roles of galectin-1 during parasitic infection and indicate an important role for this molecule in tissue-specific Th1 cell development, but not CD4+ T cell IL-10 production. © 2017 Bunn, Montes de Oca, Rivera, Kumar, Edwards, Faleiro, Ng, Sheel, Wang, Amante, Haque and Engwerda.
Human IL-10–producing Th1 cells exhibit a molecular signature distinct from Tr1 cells in malaria
(American Society for Clinical Investigation, 2023) Chelsea L. Edwards; Susanna S. Ng; Fabian de Labastida Rivera; Dillon Corvino; Jessica A. Engel; Marcela Montes de Oca; Luzia Bukali; Teija C.M. Frame; Patrick T. Bunn; Shashi Bhushan Chauhan; Siddharth Sankar Singh; Yulin Wang; Jinrui Na; Fiona H. Amante; Jessica R. Loughland; Megan S.F. Soon; Nicola Waddell; Pamela Mukhopadhay; Lambros T. Koufariotis; Rebecca L. Johnston; Jason S. Lee; Rachel Kuns; Ping Zhang; Michelle J. Boyle; Geoffrey R. Hill; James S. McCarthy; Rajiv Kumar; Christian R. Engwerda
Control of intracellular parasites responsible for malaria requires host IFN-γ+T-bet+CD4+ T cells (Th1 cells) with IL-10 produced by Th1 cells to mitigate the pathology induced by this inflammatory response. However, these IL-10–producing Th1 (induced type I regulatory [Tr1]) cells can also promote parasite persistence or impair immunity to reinfection or vaccination. Here, we identified molecular and phenotypic signatures that distinguished IL-10–Th1 cells from IL-10+Tr1 cells in Plasmodium falciparum–infected people who participated in controlled human malaria infection studies, as well as C57BL/6 mice with experimental malaria caused by P. berghei ANKA. We also identified a conserved Tr1 cell molecular signature shared between patients with malaria, dengue, and graft-versus-host disease. Genetic manipulation of primary human CD4+ T cells showed that the transcription factor cMAF played an important role in the induction of IL-10, while BLIMP-1 promoted the development of human CD4+ T cells expressing multiple coinhibitory receptors. We also describe heterogeneity of Tr1 cell coinhibitory receptor expression that has implications for targeting these molecules for clinical advantage during infection. Overall, this work provides insights into CD4+ T cell development during malaria that offer opportunities for creation of strategies to modulate CD4+ T cell functions and improve antiparasitic immunity. © 2023 American Society for Clinical Investigation. All rights reserved.
The NK cell granule protein NKG7 regulates cytotoxic granule exocytosis and inflammation
(Nature Research, 2020) Susanna S. Ng; Fabian De Labastida Rivera; Juming Yan; Dillon Corvino; Indrajit Das; Ping Zhang; Rachel Kuns; Shashi Bhushan Chauhan; Jiajie Hou; Xian-Yang Li; Teija C. M. Frame; Benjamin A. McEnroe; Eilish Moore; Jinrui Na; Jessica A. Engel; Megan S. F. Soon; Bhawana Singh; Andrew J. Kueh; Marco J. Herold; Marcela Montes de Oca; Siddharth Sankar Singh; Patrick T. Bunn; Amy Roman Aguilera; Mika Casey; Matthias Braun; Nazanin Ghazanfari; Shivangi Wani; Yulin Wang; Fiona H. Amante; Chelsea L. Edwards; Ashraful Haque; William C. Dougall; Om Prakash Singh; Alan G. Baxter; Michele W. L. Teng; Alex Loukas; Norelle L. Daly; Nicole Cloonan; Mariapia A. Degli-Esposti; Jude Uzonna; William R. Heath; Tobias Bald; Siok-Keen Tey; Kyohei Nakamura; Geoffrey R. Hill; Rajiv Kumar; Shyam Sundar; Mark J. Smyth; Christian R. Engwerda
Immune-modulating therapies have revolutionized the treatment of chronic diseases, particularly cancer. However, their success is restricted and there is a need to identify new therapeutic targets. Here, we show that natural killer cell granule protein 7 (NKG7) is a regulator of lymphocyte granule exocytosis and downstream inflammation in a broad range of diseases. NKG7 expressed by CD4+ and CD8+ T cells played key roles in promoting inflammation during visceral leishmaniasis and malaria—two important parasitic diseases. Additionally, NKG7 expressed by natural killer cells was critical for controlling cancer initiation, growth and metastasis. NKG7 function in natural killer and CD8+ T cells was linked with their ability to regulate the translocation of CD107a to the cell surface and kill cellular targets, while NKG7 also had a major impact on CD4+ T cell activation following infection. Thus, we report a novel therapeutic target expressed on a range of immune cells with functions in different immune responses. © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.
The role of BACH2 in T cells in experimental malaria caused by Plasmodium chabaudi chabaudi AS
(Frontiers Media S.A., 2018) Chelsea L. Edwards; Marcela Montes De Oca; Fabian De Labastida Rivera; Rajiv Kumar; Susanna S. Ng; Yulin Wang; Fiona H. Amante; Kohei Kometani; Tomohiro Kurosaki; Tom Sidwell; Axel Kallies; Christian R. Engwerda
BTB and CNC Homology 1, Basic Leucine Zipper Transcription Factor 2 (BACH2) is a transcription factor best known for its role in B cell development. More recently, it has been associated with T cell functions in inflammatory diseases, and has been proposed as a master transcriptional regulator within the T cell compartment. In this study, we employed T cell-specific Bach2-deficient (B6.Bach2ΔT) mice to examine the role of this transcription factor in CD4+ T cell functions in vitro and in mice infected with Plasmodium chabaudi AS. We found that under CD4+ T cell polarizing conditions in vitro, Th2, and Th17 helper cell subsets were more active in the absence of Bach2 expression. In mice infected with P. chabaudi AS, although the absence of Bach2 expression by T cells had no effect on blood parasitemia or disease pathology, we found reduced expansion of CD4+ T cells in B6.Bach2ΔT mice, compared with littermate controls. Despite this reduction, we observed increased frequencies of Tbet+ IFNγ+ CD4+ (Th1) cells and IL-10-producing Th1 (Tr1) cells in mice lacking Bach2 expression by T cells. Studies in mixed bone marrow chimeric mice revealed T cell intrinsic effects of BACH2 on hematopoietic cell development, and in particular, the generation of CD4+ and CD8+ T cell subsets. Furthermore, T cell intrinsic BACH2 was needed for efficient expansion of CD4+ T cells during experimental malaria in this immunological setting. We also examined the response of B6.Bach2ΔT mice to a second protozoan parasitic challenge with Leishmania donovani and found similar effects on disease outcome and T cell responses. Together, our findings provide new insights into the role of BACH2 in CD4+ T cell activation during experimental malaria, and highlight an important role for this transcription factor in the development and expansion of T cells under homeostatic conditions, as well as establishing the composition of the effector CD4+ T cell compartment during infection. Copyright © 2018 Edwards, de Oca, de Labastida Rivera, Kumar, Ng, Wang, Amante, Kometani, Kurosaki, Sidwell, Kallies and Engwerda. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
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)
Type I Interferons Suppress Anti-parasitic Immunity and Can Be Targeted to Improve Treatment of Visceral Leishmaniasis
(Elsevier B.V., 2020) Rajiv Kumar; Patrick T. Bunn; Siddharth Sankar Singh; Susanna S. Ng; Marcela Montes de Oca; Fabian De Labastida Rivera; Shashi Bhushan Chauhan; Neetu Singh; Rebecca J. Faleiro; Chelsea L. Edwards; Teija C.M. Frame; Meru Sheel; Rebecca J. Austin; Steven W. Lane; Tobias Bald; Mark J. Smyth; Geoffrey.R. Hill; Shannon E. Best; Ashraful Haque; Dillon Corvino; Nic Waddell; Lambross Koufariotis; Pamela Mukhopadhay; Madhukar Rai; Jaya Chakravarty; Om Prakash Singh; David Sacks; Susanne Nylen; Jude Uzonna; Shyam Sundar; Christian R. Engwerda
CD4+ T cells are critical for control of intracellular parasites such as Leishmania donovani. Kumar et al. show that type I interferons (IFNs) suppress Th1 cells and promote IL-10-producing CD4+ T cells during visceral leishmaniasis (VL). Thus, manipulation of type I IFN signaling may improve disease outcome in VL patients. © 2020 The Authors; Type I interferons (IFNs) play critical roles in anti-viral and anti-tumor immunity. However, they also suppress protective immune responses in some infectious diseases. Here, we identify type I IFNs as major upstream regulators of CD4+ T cells from visceral leishmaniasis (VL) patients. Furthermore, we report that mice deficient in type I IFN signaling have significantly improved control of Leishmania donovani, a causative agent of human VL, associated with enhanced IFNγ but reduced IL-10 production by parasite-specific CD4+ T cells. Importantly, we identify a small-molecule inhibitor that can be used to block type I IFN signaling during established infection and acts synergistically with conventional anti-parasitic drugs to improve parasite clearance and enhance anti-parasitic CD4+ T cell responses in mice and humans. Thus, manipulation of type I IFN signaling is a promising strategy for improving disease outcome in VL patients. © 2020 The Authors