Cytotoxic activities of CD8+ T cells collaborate with macrophages to protect against blood-stage murine malaria

  1. Takashi Imai
  2. Hidekazu Ishida
  3. Kazutomo Suzue
  4. Tomoyo Taniguchi
  5. Hiroko Okada
  6. Chikako Shimokawa
  7. Hajime Hisaeda  Is a corresponding author
  1. Gunma University Graduate School of Medicine, Japan
  2. Otsuka Pharmaceutical Co., Ltd, Japan
  3. RIKEN Center for Integrative Medical Science, Japan

Abstract

The protective immunity afforded by CD8+ T cells against blood-stage malaria remains controversial because no MHC class I molecules are displayed on parasite-infected human erythrocytes. We recently reported that rodent malaria parasites infect erythroblasts that express MHC class I antigens, which are recognized by CD8+ T cells. In this study, we demonstrate that the cytotoxic activity of CD8+ T cells contributes to the protection of mice against blood-stage malaria in a FasL-dependent manner. Malaria parasites infected erythroblasts express death receptor Fas. CD8+ T cells induce the externalization of phosphatidylserine (PS) on the infected erythroblasts in a cell-to-cell contact-dependent manner. PS enhances the engulfment of the infected erythroid cells by phagocytes. T-cell immunoglobulin- and mucin-domain-containing molecule (Tim-4) contributes to the phagocytosis of malaria parasites infected cells as phosphatidylserine receptor. Our findings provide insight into the molecular mechanisms underlying the protective immunity exerted by CD8+ T cells in collaboration with phagocytes.

Article and author information

Author details

  1. Takashi Imai

    Department of Parasitology, Gunma University Graduate School of Medicine, Maebashi, Japan
    Competing interests
    The authors declare that no competing interests exist.
  2. Hidekazu Ishida

    Microbiological Research Institute, Otsuka Pharmaceutical Co., Ltd, Tokushima, Japan
    Competing interests
    The authors declare that no competing interests exist.
  3. Kazutomo Suzue

    Department of Parasitology, Gunma University Graduate School of Medicine, Maebashi, Japan
    Competing interests
    The authors declare that no competing interests exist.
  4. Tomoyo Taniguchi

    Department of Parasitology, Gunma University Graduate School of Medicine, Maebashi, Japan
    Competing interests
    The authors declare that no competing interests exist.
  5. Hiroko Okada

    Department of Parasitology, Gunma University Graduate School of Medicine, Maebashi, Japan
    Competing interests
    The authors declare that no competing interests exist.
  6. Chikako Shimokawa

    Laboratory for Intestinal Ecosystem, RIKEN Center for Integrative Medical Science, Nagasaki, Japan
    Competing interests
    The authors declare that no competing interests exist.
  7. Hajime Hisaeda

    Department of Parasitology, Gunma University Graduate School of Medicine, Maebashi, Japan
    For correspondence
    0521773@gmail.com
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Ronald N Germain, National Institute of Allergy and Infectious Diseases, United States

Ethics

Animal experimentation: All mouse experiments were approved by the Committee for Ethics on Animal Experiments in the Faculty of Medicine, and performed under the control of the Guidelines for Animal Experiments in the Faculty of Medicine, Gunma University and Kyushu University, according to Japanese law (no. 105) and notification (no. 6) of the Government of Japan. No human samples were used in these experiments.

Version history

  1. Received: August 2, 2014
  2. Accepted: February 24, 2015
  3. Accepted Manuscript published: March 11, 2015 (version 1)
  4. Version of Record published: March 20, 2015 (version 2)

Copyright

© 2015, Imai et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 2,960
    Page views
  • 490
    Downloads
  • 47
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, Scopus, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Takashi Imai
  2. Hidekazu Ishida
  3. Kazutomo Suzue
  4. Tomoyo Taniguchi
  5. Hiroko Okada
  6. Chikako Shimokawa
  7. Hajime Hisaeda
(2015)
Cytotoxic activities of CD8+ T cells collaborate with macrophages to protect against blood-stage murine malaria
eLife 4:e04232.
https://doi.org/10.7554/eLife.04232

Share this article

https://doi.org/10.7554/eLife.04232

Further reading

    1. Developmental Biology
    2. Immunology and Inflammation
    Amir Hossein Kayvanjoo, Iva Splichalova ... Elvira Mass
    Research Article

    During embryogenesis, the fetal liver becomes the main hematopoietic organ, where stem and progenitor cells as well as immature and mature immune cells form an intricate cellular network. Hematopoietic stem cells (HSCs) reside in a specialized niche, which is essential for their proliferation and differentiation. However, the cellular and molecular determinants contributing to this fetal HSC niche remain largely unknown. Macrophages are the first differentiated hematopoietic cells found in the developing liver, where they are important for fetal erythropoiesis by promoting erythrocyte maturation and phagocytosing expelled nuclei. Yet, whether macrophages play a role in fetal hematopoiesis beyond serving as a niche for maturing erythroblasts remains elusive. Here, we investigate the heterogeneity of macrophage populations in the murine fetal liver to define their specific roles during hematopoiesis. Using a single-cell omics approach combined with spatial proteomics and genetic fate-mapping models, we found that fetal liver macrophages cluster into distinct yolk sac-derived subpopulations and that long-term HSCs are interacting preferentially with one of the macrophage subpopulations. Fetal livers lacking macrophages show a delay in erythropoiesis and have an increased number of granulocytes, which can be attributed to transcriptional reprogramming and altered differentiation potential of long-term HSCs. Together, our data provide a detailed map of fetal liver macrophage subpopulations and implicate macrophages as part of the fetal HSC niche.

    1. Immunology and Inflammation
    2. Microbiology and Infectious Disease
    Yuting Zhang, Min Zhang ... Guojiang Chen
    Research Article

    Marburg virus (MARV) is one of the filovirus species that cause deadly hemorrhagic fever in humans, with mortality rates up to 90%. Neutralizing antibodies represent ideal candidates to prevent or treat virus disease. However, no antibody has been approved for MARV treatment to date. In this study, we identified a novel human antibody named AF-03 that targeted MARV glycoprotein (GP). AF-03 possessed a high binding affinity to MARV GP and showed neutralizing and protective activities against the pseudotyped MARV in vitro and in vivo. Epitope identification, including molecular docking and experiment-based analysis of mutated species, revealed that AF-03 recognized the Niemann-Pick C1 (NPC1) binding domain within GP1. Interestingly, we found the neutralizing activity of AF-03 to pseudotyped Ebola viruses (EBOV, SUDV, and BDBV) harboring cleaved GP instead of full-length GP. Furthermore, NPC2-fused AF-03 exhibited neutralizing activity to several filovirus species and EBOV mutants via binding to CI-MPR. In conclusion, this work demonstrates that AF-03 represents a promising therapeutic cargo for filovirus-caused disease.