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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


Fernandez-Ruiz, D; Lau, LS; Ghazanfari, N; Jones, CM; Ng, WY; Davey, GM; Berthold, D; Holz, L; Kato, Y; Enders, MH; Bayarsaikhan, G; Hendriks, SH; Lansink, LIM; Engel, JA; Soon, MSF; James, KR; Cozijnsen, A; Mollard, V; Uboldi, AD; Tonkin, CJ; de Koning-Ward, TF; Gilson, PR; Kaisho, T; Haque, A; Crabb, BS; Carbone, FR; McFadden, GI; Heath, WR
2017-10-30
Journal of Immunology
Journal Article in press
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.
ASI
Infection and Immunity
10.4049/jimmunol.1700186
29084838
Refer to copyright notice on published article.

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Creation Date 2017-11-29 08:58:02 Last Modified 2020-04-07 02:02:47