Author's School

Graduate School of Arts & Sciences

Author's Department/Program

Biology and Biomedical Sciences: Immunology

Language

English (en)

Date of Award

8-13-2012

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Chair and Committee

Robert D Schreiber

Abstract

Host responsiveness to IFNg is critical for resolution of Listeria infection, but the identities and roles of IFNg responsive cells that initiate this process remain unclear. In this thesis, unique mice displaying conditional loss of the IFNg receptor: Ifngr1f/f mice) in different tissues have been generated and used to explore the role of this cytokine in initiating the anti-Listeria response.

Whereas Ifngr1f/f mice displayed normal cellular levels of IFNGR1 and normal resistance to Listeria infection, Vav-icre+Ifngr1f/f mice lacking IFNg responsiveness selectively in hematopoietic cells exhibited highly increased susceptibility to Listeria infection comparable to that of Ifngr1-/- mice. In contrast, Itgax-cre+ Ifngr1f/f mice lacking IFNg responsiveness selectively in dendritic cells expressing CD8a and/or CD103 displayed increased susceptibility to Listeria infection. This phenotype was traced back to a defect in the capacity of IFNg unresponsive CD8a+ DCs to produce IL-12. The IFNg required for priming CD8a+ DCs for optimal IL-12 production is derived from TNFa-activated NK/NKT cells. These mice survived Listeria infection due to a second wave of IL-12 produced by other myeloid cells.

Next, Ifngr1f/f mice were bred with LysM-cre mice to obtain myeloid cell specific Ifngr1 deletion. LysM-cre+Ifngr1f/f mice lacking IFNg responsiveness selectively in both peritoneal macrophages and neutrophils succumbed to Listeria infection. Surprisingly, adoptively transferred WT neutrophils into LysM-cre+Ifngr1f/f mice seemed to completely rescue LysM-cre+Ifngr1f/f mice whereas Ifngr1-/- neutrophils did not. Thus, these results reveal that neutrophils are also one of the important targets of IFNg for Listeria resolution.

This study thus demonstrates an early acting, IFNg driven cytokine and cellular cascade involving NK/NKT and CD8a+ DCs leads to rapid production of IL-12 that ultimately leads to activation of myeloid cells including macrophages and neutrophils in IFNg-rich cytokine environment.

DOI

https://doi.org/10.7936/K74Q7S0W

Comments

Permanent URL: http://dx.doi.org/10.7936/K74Q7S0W

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