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

Daniel Fernandez-Ruiz, Lei Shong Lau, Nazanin Ghazanfari, Claerwen M. Jones, Wei Yi Ng, Gayle M. Davey, Dorothee Berthold, Lauren Holz, Yu Kato, Matthias H. Enders, Ganchimeg Bayarsaikhan, Sanne H. Hendriks, Lianne I.M. Lansink, Jessica A. Engel, Megan S.F. Soon, Kylie R. James, Anton Cozijnsen, Vanessa Mollard, Alessandro D. Uboldi, Christopher J. TonkinTania F. De Koning-Ward, Paul R. Gilson, Tsuneyasu Kaisho, Ashraful Haque, Brendan S. Crabb, Francis R. Carbone, Geoffrey I. McFadden, William R. Heath

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10 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)4165-4179
Number of pages15
JournalJournal of Immunology
Volume199
Issue number12
DOIs
Publication statusPublished - 15 Dec 2017
Externally publishedYes

Keywords

  • experimental cerebral malaria
  • plasmodium-berghei infection
  • CXC chemokine receptor-5
  • cytotoxic T-cells
  • in-vivo protective immunity
  • cutting edge
  • antigen presentation
  • antibody-responses
  • cross-presentation

Cite this

Fernandez-Ruiz, D., Lau, L. S., Ghazanfari, N., Jones, C. M., Ng, W. Y., Davey, G. M., Berthold, D., Holz, L., Kato, Y., Enders, M. H., Bayarsaikhan, G., Hendriks, S. H., Lansink, L. I. M., Engel, J. A., Soon, M. S. F., James, K. R., Cozijnsen, A., Mollard, V., Uboldi, A. D., ... Heath, W. R. (2017). 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. Journal of Immunology, 199(12), 4165-4179. https://doi.org/10.4049/jimmunol.1700186