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

作者：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

来源：The Journal of Immunology, 2017, 199(12): 4165-4179.

DOI：10.4049/jimmunol.1700186

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.

• 出版日期2017-12-15