QIMR Berghofer

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

Abstract

We describe an MHC class II (I-A(b))-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.

Authors Fernandez-Ruiz, Daniel; Lau, Lei Shong; Ghazanfari, Nazanin; Jones, Claerwen M.; Ng, Wei Yi; Davey, Gayle M.; Berthold, Dorothee; Holz, Lauren; Kato, Yu; Enders, Matthias H.; Bayarsaikhan, Ganchimeg; Hendriks, Sanne H.; Lansink, Lianne I. M.; Engel, Jessica A.; Soon, Megan S. F.; James, Kylie R.; Cozijnsen, Anton; Mollard, Vanessa; Uboldi, Alessandro D.; Tonkin, Christopher J.; de Koning-Ward, Tania F.; Gilson, Paul R.; Kaisho, Tsuneyasu; Haque, Ashraful; Crabb, Brendan S.; Carbone, Francis R.; McFadden, Geoffrey I.; Heath, William R.
Journal JOURNAL OF IMMUNOLOGY
Pages 4165-4179
Volume 199
Date 1/12/2017
Grant ID
Funding Body National Health and Medical Research Council of Australia
URL http://www.ncbi.nlm.nih.gov/pubmed/?term=10.4049/jimmunol.1700186