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The BXH2 mutation in IRF8 differentially impairs dendritic cell subset development in the mouse
Prafullakumar Tailor1, Tomohiko Tamura, Herbert C Morse
1Laboratory of Molecular Growth Regulation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892-2753, USA.
Blood
|December 7, 2007
Summary
A mutation in interferon regulatory factor 8 (IRF8) impairs CD8alpha(+) dendritic cell (DC) development and IL12 production but not plasmacytoid DC (pDC) function. This reveals distinct roles for IRF8 in DC subset development.
Area of Science:
- Immunology
- Cell Biology
- Genetics
Background:
- Dendritic cells (DCs) are crucial for innate immunity.
- CD8alpha(+) DCs and plasmacytoid DCs (pDCs) are key DC subsets with distinct immune functions.
- Interferon regulatory factor 8 (IRF8) is essential for the development of both CD8alpha(+) DCs and pDCs.
Purpose of the Study:
- To investigate the functional consequences of a specific IRF8 mutation (IRF8(R294C)) on DC development and function.
- To elucidate the role of IRF8-partner interactions in the development of distinct DC subsets.
Main Methods:
- Analysis of the IRF8(R294C) mutation in BXH2 mice.
- Assessment of CD8alpha(+) DC and pDC development and function.
- Evaluation of IL12 and type I Interferon (IFN) production.
- Electrophoretic mobility shift assays (EMSAs) and chromatin immunoprecipitation (ChIP) assays to study IRF8 protein interactions.
Main Results:
- The IRF8(R294C) mutation abolished CD8alpha(+) DC development while sparing pDC development.
- IL12p40 production was eliminated, but type I IFN production was retained in IRF8(R294C) mutant mice.
- IRF8(R294C) protein failed to interact with partner transcription factors and bind target promoters, indicating impaired DNA binding and protein-protein interactions.
Conclusions:
- IRF8-partner interactions play distinct roles in the development of CD8alpha(+) DCs and pDCs.
- This study reveals a mechanistic separation in DC subset development governed by IRF8.
- The findings provide insights into the molecular mechanisms underlying DC subset differentiation and immune responses.
