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J Immunol. 2017 Dec 15;199(12):4165-4179. doi: 10.4049/jimmunol.1700186. Epub 2017 Oct 30.

Development of a Novel CD4+ TCR Transgenic Line That Reveals a Dominant Role for CD8+ Dendritic Cells and CD40 Signaling in the Generation of Helper and CTL Responses to Blood-Stage Malaria.

Author information

1
Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, Victoria 3000, Australia.
2
Australian Research Council Centre of Excellence in Advanced Molecular Imaging, The University of Melbourne, Parkville, Victoria 3010, Australia.
3
Division of Immunology, Department of Molecular Microbiology and Immunology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8523, Japan.
4
Malaria Immunology Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia.
5
School of BioSciences, The University of Melbourne, Parkville, Victoria 3010, Australia.
6
Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.
7
School of Medicine, Deakin University, Waurn Ponds, Victoria 3216, Australia.
8
Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, Victoria 3004, Australia; and.
9
Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama 641-8509, Japan.
10
Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, Victoria 3000, Australia; wrheath@unimelb.edu.au.

Abstract

We describe an MHC class II (I-Ab)-restricted TCR transgenic mouse line that produces CD4+ T cells specific for Plasmodium species. This line, termed PbT-II, was derived from a CD4+ T cell hybridoma generated to blood-stage Plasmodium berghei ANKA (PbA). PbT-II cells responded to all Plasmodium species and stages tested so far, including rodent (PbA, P. berghei NK65, Plasmodium chabaudi AS, and Plasmodium yoelii 17XNL) and human (Plasmodium falciparum) blood-stage parasites as well as irradiated PbA sporozoites. PbT-II cells can provide help for generation of Ab to P. chabaudi infection and can control this otherwise lethal infection in CD40L-deficient mice. PbT-II cells can also provide help for development of CD8+ T cell-mediated experimental cerebral malaria (ECM) during PbA infection. Using PbT-II CD4+ T cells and the previously described PbT-I CD8+ T cells, we determined the dendritic cell (DC) subsets responsible for immunity to PbA blood-stage infection. CD8+ DC (a subset of XCR1+ DC) were the major APC responsible for activation of both T cell subsets, although other DC also contributed to CD4+ T cell responses. Depletion of CD8+ DC at the beginning of infection prevented ECM development and impaired both Th1 and follicular Th cell responses; in contrast, late depletion did not affect ECM. This study describes a novel and versatile tool for examining CD4+ T cell immunity during malaria and provides evidence that CD4+ T cell help, acting via CD40L signaling, can promote immunity or pathology to blood-stage malaria largely through Ag presentation by CD8+ DC.

PMID:
29084838
PMCID:
PMC5713497
DOI:
10.4049/jimmunol.1700186
[Indexed for MEDLINE]
Free PMC Article

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