Browsing by Author "Dillon Corvino"

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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.
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.
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.
Increased amphiregulin expression by CD4+ T cells from individuals with asymptomatic Leishmania donovani infection
(John Wiley and Sons Inc, 2022) Siddharth Sankar Singh; Shashi Bhushan Chauhan; Susanna SS Ng; Dillon Corvino; Fabian de Labastida Rivera; Jessica A Engel; Nic Waddell; Pamela Mukhopadhay; Rebecca L Johnston; Lambros T Koufariotis; Susanne Nylen; Om Prakash Singh; Christian R Engwerda; Rajiv Kumar; Shyam Sundar
Objectives: There is an urgent need to be able to identify individuals with asymptomatic Leishmania donovani infection, so their risk of progressing to VL and transmitting parasites can be managed. This study examined transcriptional markers expressed by CD4+ T cells that could distinguish asymptomatic individuals from endemic controls and visceral leishmaniasis (VL) patients. Methods: CD4+ T cells were isolated from individuals with asymptomatic L. donovani infection, endemic controls and VL patients. RNA was extracted and RNAseq employed to identify differentially expressed genes. The expression of one gene and its protein product during asymptomatic infection were evaluated. Results: Amphiregulin (AREG) was identified as a distinguishing gene product in CD4+ T cells from individuals with asymptomatic L. donovani infection, compared to VL patients and healthy endemic control individuals. AREG levels in plasma and antigen-stimulated whole-blood assay cell culture supernatants were significantly elevated in asymptomatic individuals, compared to endemic controls and VL patients. Regulatory T (Treg) cells were identified as an important source of AREG amongst CD4+ T-cell subsets in asymptomatic individuals. Conclusion: Increased Treg cell AREG expression was identified in individuals with asymptomatic L. donovani infection, suggesting the presence of an ongoing inflammatory response in these individuals required for controlling infection and that AREG may play an important role in preventing inflammation-induced tissue damage and subsequent disease in asymptomatic individuals. © 2022 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand 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.
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