Browsing by Author "Teija C.M. Frame"

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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.
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.
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.
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