Browsing by Author "Susanna Ng"

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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
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.
The role of IL-10 in malaria: A double edged sword
(Frontiers Media S.A., 2019) Rajiv Kumar; Susanna Ng; Christian Engwerda
IL-10 produced by CD4+ T cells suppresses inflammation by inhibiting T cell functions and the upstream activities of antigen presenting cells (APCs). IL-10 was first identified in Th2 cells, but has since been described in IFNγ-producing Tbet+ Th1, FoxP3+ CD4+ regulatory T (Treg) and IL-17-producing CD4+ T (Th17) cells, as well as many innate and innate-like immune cell populations. IL-10 production by Th1 cells has emerged as an important mechanism to dampen inflammation in the face of intractable infection, including in African children with malaria. However, although these type I regulatory T (Tr1) cells protect tissue from inflammation, they may also promote disease by suppressing Th1 cell-mediated immunity, thereby allowing infection to persist. IL-10 produced by other immune cells during malaria can also influence disease outcome, but the full impact of this IL-10 production is still unclear. Together, the actions of this potent anti-inflammatory cytokine along with other immunoregulatory mechanisms that emerge following Plasmodium infection represent a potential hurdle for the development of immunity against malaria, whether naturally acquired or vaccine-induced. Recent advances in understanding how IL-10 production is initiated and regulated have revealed new opportunities for manipulating IL-10 for therapeutic advantage. In this review, we will summarize our current knowledge about IL-10 production during malaria and discuss its impact on disease outcome. We will highlight recent advances in our understanding about how IL-10 production by specific immune cell subsets is regulated and consider how this knowledge may be used in drug delivery and vaccination strategies to help eliminate malaria. Copyright © 2019 Kumar, Ng 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.