RT Journal Article
SR Electronic
T1 Development of a Novel CD4<sup>+</sup> TCR Transgenic Line that Reveals a Dominant Role for CD8<sup>+</sup> DC and CD40-Signaling in the Generation of Helper and CTL Responses to Blood Stage Malaria
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 113837
DO 10.1101/113837
A1 Daniel Fernandez-Ruiz
A1 Lei Shong Lau
A1 Nazanin Ghazanfari
A1 Claerwen M Jones
A1 Wei Yi Ng
A1 Gayle M Davey
A1 Dorothee Berthold
A1 Lauren Holz
A1 Yu Kato
A1 Ganchimeg Bayarsaikhan
A1 Sanne H. Hendriks
A1 Kylie R James
A1 Anton Cozijnsen
A1 Vanessa Mollard
A1 Tania F de Koning-Ward
A1 Paul R Gilson
A1 Tsuneyasu Kaisho
A1 Ashraful Haque
A1 Brendan S Crabb
A1 Francis R Carbone
A1 Geoffrey I. McFadden
A1 William R Heath
YR 2017
UL http://biorxiv.org/content/early/2017/03/03/113837.abstract
AB We describe an MHC II (IAb)-restricted T cell receptor (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, P. chabaudi AS and P. yoelii 17XNL) and human (P. falciparum) blood-stage parasites as well as irradiated PbA sporozoites. PbT-II cells can provide help for generation of antibody 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 antigen presenting cell (APC) responsible for activation of both T cell subsets, though 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 Tfh 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 signalling, can promote immunity or pathology to blood stage malaria largely through antigen presentation by CD8+ DC.