Author's School

Graduate School of Arts & Sciences

Author's Department/Program

Biology and Biomedical Sciences: Immunology

Language

English (en)

Date of Award

Spring 3-4-2013

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Chair and Committee

Kenneth M Murphy

Abstract

CD8α+ dendritic cells are important in vivo for cross-presentation of antigens derived from intracellular pathogens and tumors. Additionally, stimulation of IL-12 production by CD8α+ DCs has suggested a role for these cells in response to Toxoplasma gondii antigens, although no experiments have yet shown an in vivo requirement for these cells against T. gondii infection. Towards this goal, we examined T. gondii infection of Batf3-/- mice, which selectively lack only lymphoid-resident CD8α+ DCs and related peripheral CD103+ DCs. Batf3-/- mice were extremely susceptible to T. gondii infection, with defective priming of CD8+ T cells, and decreased production of IL-12 and IFNγ. IL-12 administration restored resistance in Batf3-/- mice, and mice in which IL-12 production was ablated only from CD8α+ DCs failed to control infection. These results reveal that the function of CD8α+ DCs extends beyond a role in cross-presentation and includes a critical role for activation of innate immunity through IL-12 production during T. gondii infection.

While investigating the immune responses of Batf3-/- mice to T. gondii infection, we made the surprising discovery that IL-12 treatment of infected Batf3-/- mice resulted in re-appearance of the CD8α+ DC population in the spleen. In addition, we show that IL-12-treatment alone in the absence of infection restored the CD8α+ DC population in Batf3-/- mice. Analysis of the restored cells by microarray revealed very few differences in gene expression between wild-type and IL-12-induced Batf3-/- CD8α+ DCs. Furthermore, IL-12 treatment of Batf3-/- mice restored their capacity for in vivo cross-presentation of necrotic cell-associated antigens. Finally, the restored CD8α+ DCs primed CD8+ T cells against T. gondii-derived antigen, and produced IL-12 in vivo in response to T. gondii infection. Thus, IL-12 can induce development of CD8α+ DCs through a Batf3-independent mechanism, and these cells can function to both prime T cells as well as produce IL-12 during infection in vivo.

DOI

https://doi.org/10.7936/K7RJ4GG5

Comments

Permanent URL: http://dx.doi.org/10.7936/K7RJ4GG5

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