Browsing by Author "Fabian de Labastida Rivera"

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A molecular signature for CD8+ T cells from visceral leishmaniasis patients
(Blackwell Publishing Ltd, 2019) Bhawana Singh; Shashi Bhushan Chauhan; Rajiv Kumar; Siddharth Sankar Singh; Susanna Ng; Fiona Amante; Fabian de Labastida Rivera; Om Prakash Singh; Madhukar Rai; Susanne Nylen; Shyam Sundar; Christian Engwerda
CD8+ T-cell function is compromised in chronic diseases such as visceral leishmaniasis (VL). However, little is known about the changes in gene expression that cause CD8+ T-cell dysfunction during VL. We used targeted transcriptional profiling of peripheral blood CD8+ T cells from VL patients pre- and post-anti-parasitic drug treatment, and compared them with the same cell population from healthy endemic controls to assess their activation, differentiation and functional status during disease. We found a predominance of downregulated immune genes in CD8+ T cells from VL patients. However, genes encoding several notable immune checkpoint molecules, including LAG-3, TIM-3 and CTLA-4, cytolytic molecules, such as granzymes A, B and H and perforin, as well as SOCS3, STAT1, JAK2 and JAK3 cytokine signalling genes were found to be increasingly expressed by VL patient CD8+ T cells. Additional studies confirmed increased expression of the inhibitory receptors LAG3 and TIM3 on VL patient CD8+ T cells, thereby identifying these molecules as potential targets to improve antigen-specific CD8+ T-cell responses during disease. © 2019 John Wiley & Sons Ltd
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.
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.
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.
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)