Batf3-Deficient Mice: Susceptibility to Toxoplasma gondii and Responses to IL-12 Treatment in vivo

<p>CD8&alpha;<super>+</super> dendritic cells are important <italic>in vivo</italic> for cross-presentation of antigens derived from intracellular pathogens and tumors. Additionally, stimulation of IL-12 production by CD8&alpha;<super>+</super> DCs has suggested a role for these cells in response to <italic>Toxoplasma gondii</italic> antigens, although no experiments have yet shown an <italic>in vivo</italic> requirement for these cells against <italic>T. gondii</italic> infection. Towards this goal, we examined <italic>T. gondii</italic> infection of Batf3<super>-/-</super> mice, which selectively lack only lymphoid-resident CD8&alpha;<super>+</super> DCs and related peripheral CD103<super>+</super> DCs. Batf3<super>-/-</super> mice were extremely susceptible to <italic>T. gondii</italic> infection, with defective priming of CD8<super>+</super> T cells, and decreased production of IL-12 and IFN&gamma;. IL-12 administration restored resistance in Batf3<super>-/-</super> mice, and mice in which IL-12 production was ablated only from CD8&alpha;<super>+</super> DCs failed to control infection. These results reveal that the function of CD8&alpha;<super>+</super> DCs extends beyond a role in cross-presentation and includes a critical role for activation of innate immunity through IL-12 production during <italic>T. gondii</italic> infection.</p><p>While investigating the immune responses of Batf3<super>-/-</super> mice to <italic>T. gondii</italic> infection, we made the surprising discovery that IL-12 treatment of infected Batf3<super>-/-</super> mice resulted in re-appearance of the CD8&alpha;<super>+</super> DC population in the spleen. In addition, we show that IL-12-treatment alone in the absence of infection restored the CD8&alpha;<super>+</super> DC population in Batf3<super>-/-</super> mice. Analysis of the restored cells by microarray revealed very few differences in gene expression between wild-type and IL-12-induced Batf3<super>-/-</super> CD8&alpha;<super>+</super> DCs. Furthermore, IL-12 treatment of Batf3<super>-/-</super> mice restored their capacity for <italic>in vivo</italic> cross-presentation of necrotic cell-associated antigens. Finally, the restored CD8&alpha;<super>+</super> DCs primed CD8<super>+</super> T cells against <italic>T. gondii</italic>-derived antigen, and produced IL-12 <italic>in vivo</italic> in response to <italic>T. gondii</italic> infection. Thus, IL-12 can induce development of CD8&alpha;<super>+</super> DCs through a Batf3-independent mechanism, and these cells can function to both prime T cells as well as produce IL-12 during infection <italic>in vivo</italic>.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Biology and Biomedical Sciences: Immunology

Year dc:date.available

2013

Author dc:creator

• Mashayekhi, Mona

Contributors dc:contributor

• Kenneth M Murphy

• Batf3
• CD8-alpha+ dendritic cells
• IL-12
• Toxoplasma gondii
• Immunology and Infectious Disease

Language dc:language

English (en)

DOI

https://doi.org/10.7936/K7RJ4GG5

OAI identifier oai:identifier

oai:openscholarship.wustl.edu:etd-2054