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

• Published in: The Journal of immunology (1950) Vol. 199; no. 12; pp. 4165 - 4179
• Main 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
• Format: Journal Article
• Language: English
• Published: United States American Association of Immunologists 15.12.2017; AAI
• Subjects: Antigen presentation; Antigen-presenting cells; Blood; CD4 antigen; CD40 antigen; CD40L protein; CD8 antigen; Cell activation; Cytotoxicity; Dendritic cells; Depletion; Extracellular matrix; Infections; Lymphocytes; Lymphocytes T; Major histocompatibility complex; Malaria; Novel Immunological Methods; Parasites; Plasmodium; Polybutylene terephthalates; Rodents; Sporozoites; T cell receptors; Transgenic mice; Vector-borne diseases
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1700186

We describe an MHC class II (I-A )-restricted TCR transgenic mouse line that produces CD4 T cells specific for species. This line, termed PbT-II, was derived from a CD4 T cell hybridoma generated to blood-stage ANKA (PbA). PbT-II cells responded to all species and stages tested so far, including rodent (PbA, NK65, AS, and 17XNL) and human ( ) blood-stage parasites as well as irradiated PbA sporozoites. PbT-II cells can provide help for generation of Ab to 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.