IFNγ and IL-12 Restrict Th2 Responses during Helminth/Plasmodium Co-Infection and Promote IFNγ from Th2 Cells

RESEARCH ARTICLE IFNγ and IL-12 Restrict Th2 Responses during Helminth/Plasmodium Co-Infection and Promote IFNγ from Th2 Cells Stephanie M. Coomes1, Victoria S. Pelly1, Yashaswini Kannan1, Isobel S. Okoye1, Stephanie Czieso1, Lewis J. Entwistle1, Jimena Perez-Lloret1, Nikolay Nikolov2, Alexandre J. Potocnik1¤, Judit Biró1, Jean Langhorne3, Mark S. Wilson1* 1 Division of Molecular Immunology, The Francis Crick Institute, London, United Kingdom, 2 Division of Systems Biology, The Francis Crick Institute, London, United Kingdom, 3 Division of Parasitology, Mill Hill Laboratories, London, United Kingdom ¤ Current Address: Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, United Kingdom * Abstract OPEN ACCESS Citation: Coomes SM, Pelly VS, Kannan Y, Okoye IS, Czieso S, Entwistle LJ, et al. (2015) IFNγ and IL12 Restrict Th2 Responses during Helminth/ Plasmodium Co-Infection and Promote IFNγ from Th2 Cells. PLoS Pathog 11(7): e1004994. doi:10.1371/journal.ppat.1004994 Editor: Adrian Paul Mountford, University of York, UNITED KINGDOM Received: October 10, 2014 Accepted: June 2, 2015 Published: July 6, 2015 Copyright: © 2015 Coomes et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All relevant data are within the paper and its Supporting Information files. Funding: This work was supported by the Medical Research Council (MRC File Reference number MC_UP_A253_1028). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Parasitic helminths establish chronic infections in mammalian hosts. Helminth/Plasmodium co-infections occur frequently in endemic areas. However, it is unclear whether Plasmodium infections compromise anti-helminth immunity, contributing to the chronicity of infection. Immunity to Plasmodium or helminths requires divergent CD4+ T cell-driven responses, dominated by IFNγ or IL-4, respectively. Recent literature has indicated that Th cells, including Th2 cells, have phenotypic plasticity with the ability to produce non-lineage associated cytokines. Whether such plasticity occurs during co-infection is unclear. In this study, we observed reduced anti-helminth Th2 cell responses and compromised anti-helminth immunity during Heligmosomoides polygyrus and Plasmodium chabaudi co-infection. Using newly established triple cytokine reporter mice (Il4gfpIfngyfpIl17aFP635), we demonstrated that Il4gfp+ Th2 cells purified from in vitro cultures or isolated ex vivo from helminthinfected mice up-regulated IFNγ following adoptive transfer into Rag1–/– mice infected with P. chabaudi. Functionally, Th2 cells that up-regulated IFNγ were transcriptionally re-wired and protected recipient mice from high parasitemia. Mechanistically, TCR stimulation and responsiveness to IL-12 and IFNγ, but not type I IFN, was required for optimal IFNγ production by Th2 cells. Finally, blockade of IL-12 and IFNγ during co-infection partially preserved anti-helminth Th2 responses. In summary, this study demonstrates that Th2 cells retain substantial plasticity with the ability to produce IFNγ during Plasmodium infection. Consequently, co-infection with Plasmodium spp. may contribute to the chronicity of helminth infection by reducing anti-helminth Th2 cells and converting them into IFNγ-secreting cells. Competing Interests: The authors have declared that no competing interests exist. PLOS Pathogens | DOI:10.1371/journal.ppat.1004994 July 6, 2015 1 / 29 Th2 Cells Produce IFNγ during Plasmodium Infection Author Summary Approximately a third of the world’s population is burdened with chronic intestinal parasitic helminth infections, causing significant morbidities. Identifying the factors that contribute to the chronicity of infection is therefore essential. Co-infection with other pathogens, which is extremely common in helminth endemic areas, may contribute to the chronicity of helminth infections. In this study, we used a mouse model to test whether the immune responses to an intestinal helminth were impaired following malaria co-infection. These two pathogens induce very different immune responses, which, until recently, were thought to be opposing and non-interchangeable. This study identified that the immune cells required for anti-helminth responses are capable of changing their phenotype and providing protection against malaria. By identifying and blocking the factors that drive this change in phenotype, we can preserve anti-helminth immune responses during coinfection. Our studies provide fresh insight into how immune responses are altered during helminth and malaria co-infection. Introduction Infections with Plasmodium and helminths are extremely common, each contributing to substantial morbidity in affected populations [1–3]. Additionally, co-infections with Plasmodium species and intestinal helminths occur frequently in co-endemic areas [4,5]. The impact of coinfection on disease burden, pathogenesis, resistance to infection and immunity is complex and poorly understood. The vast majority of reported co-infection studies have focused on the impact of helminth infection on Plasmodium-associated responses, identifying altered antimalarial immune responses or malaria-associated pathology during helminth co-infection [6– 11]. However, the specific impact of Plasmodium infection on anti-helminth immunity has not been well characterized. Experimental murine models of helminth and Plasmodium co-infections have been established, however these have also mainly focused on how concomitant helminth infection affects Plasmodium immunity and pathology [11–16], with much less focus on how Plasmodium infection impacts helminth-associated type 2 responses. Murine models of intestinal helminth infections have delineated a clear role for Th2-directed immune responses for proficient immunity. In particular, infection with the natural murine helminth, Heligmosomoides polygyrus, results in a chronic infection with the induction of a polarized type 2 response, characterized by IL-4-producing Th2 cells, alternative activation of macrophages and elevated IgE, closely mimicking human helminthiasis. Following anthelmintic treatment, Th2 cell-dependent immunity protects mice from re-infection (reviewed in [17,18]). In contrast, acute blood-stage infection with the rodent malaria parasite, Plasmodium chabaudi chabaudi (AS), results in polyclonal lymphocyte activation with a strongly polarized Th1 response [19]. Disease is associated with a spectrum of immunopathologies including splenomegaly and anemia [20–22] with peak parasitemia occurring 7–9 days post-infection [23]. These well-studied experimental systems, modeling human disease, provide appropriate tools to dissect the immune respons (...truncated)