Browsing by Author "Fabian De Labastida Rivera"

Now showing 1 - 7 of 7

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.
Interleukin 2 is an Upstream Regulator of CD4+ T Cells from Visceral Leishmaniasis Patients with Therapeutic Potential
(Oxford University Press, 2019) Shashi Bhushan Chauhan; Rebecca Faleiro; Rajiv Kumar; Susanna Ng; Bhawana Singh; Om Prakash Singh; Siddharth Sankar Singh; Fiona Amante; Fabian De Labastida Rivera; Madhukar Rai; Jaya Chakravarty; David Sacks; Susanne Nylen; Shyam Sundar; Christian Engwerda
Control of visceral leishmaniasis (VL) caused by Leishmania donovani requires interferon-γproduction by CD4+ T cells. In VL patients, antiparasitic CD4+ T-cell responses are ineffective for unknown reasons. In this study, we measured the expression of genes associated with various immune functions in these cells from VL patients and compared them to CD4+ T cells from the same patients after drug treatment and from endemic controls. We found reduced GATA3, RORC, and FOXP3 gene expression in CD4+ T cells of VL patients, associated with reduced Th2, Th17, and FOXP3+CD4+ T regulatory cell frequencies in VL patient blood. Interleukin 2 (IL-2) was an important upstream regulator of CD4+ T cells from VL patients, and functional studies demonstrated the therapeutic potential of IL-2 for improving antiparasitic immunity. Together, these results provide new insights into the characteristics of CD4+ T cells from VL patients that can be used to improve antiparasitic immune responses. © 2019 The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.
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.
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 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