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1.  Novel insights into the relationships between dendritic cell subsets in human and mouse revealed by genome-wide expression profiling 
Genome Biology  2008;9(1):R17.
Genome-wide expression profiling of mouse and human leukocytes reveal conserved transcriptional programs of plasmacytoid or conventional dendritic cell subsets.
Background
Dendritic cells (DCs) are a complex group of cells that play a critical role in vertebrate immunity. Lymph-node resident DCs (LN-DCs) are subdivided into conventional DC (cDC) subsets (CD11b and CD8α in mouse; BDCA1 and BDCA3 in human) and plasmacytoid DCs (pDCs). It is currently unclear if these various DC populations belong to a unique hematopoietic lineage and if the subsets identified in the mouse and human systems are evolutionary homologs. To gain novel insights into these questions, we sought conserved genetic signatures for LN-DCs and in vitro derived granulocyte-macrophage colony stimulating factor (GM-CSF) DCs through the analysis of a compendium of genome-wide expression profiles of mouse or human leukocytes.
Results
We show through clustering analysis that all LN-DC subsets form a distinct branch within the leukocyte family tree, and reveal a transcriptomal signature evolutionarily conserved in all LN-DC subsets. Moreover, we identify a large gene expression program shared between mouse and human pDCs, and smaller conserved profiles shared between mouse and human LN-cDC subsets. Importantly, most of these genes have not been previously associated with DC function and many have unknown functions. Finally, we use compendium analysis to re-evaluate the classification of interferon-producing killer DCs, lin-CD16+HLA-DR+ cells and in vitro derived GM-CSF DCs, and show that these cells are more closely linked to natural killer and myeloid cells, respectively.
Conclusion
Our study provides a unique database resource for future investigation of the evolutionarily conserved molecular pathways governing the ontogeny and functions of leukocyte subsets, especially DCs.
doi:10.1186/gb-2008-9-1-r17
PMCID: PMC2395256  PMID: 18218067
2.  Natural Killer Cells Promote Early CD8 T Cell Responses against Cytomegalovirus 
PLoS Pathogens  2007;3(8):e123.
Understanding the mechanisms that help promote protective immune responses to pathogens is a major challenge in biomedical research and an important goal for the design of innovative therapeutic or vaccination strategies. While natural killer (NK) cells can directly contribute to the control of viral replication, whether, and how, they may help orchestrate global antiviral defense is largely unknown. To address this question, we took advantage of the well-defined molecular interactions involved in the recognition of mouse cytomegalovirus (MCMV) by NK cells. By using congenic or mutant mice and wild-type versus genetically engineered viruses, we examined the consequences on antiviral CD8 T cell responses of specific defects in the ability of the NK cells to control MCMV. This system allowed us to demonstrate, to our knowledge for the first time, that NK cells accelerate CD8 T cell responses against a viral infection in vivo. Moreover, we identify the underlying mechanism as the ability of NK cells to limit IFN-α/β production to levels not immunosuppressive to the host. This is achieved through the early control of cytomegalovirus, which dramatically reduces the activation of plasmacytoid dendritic cells (pDCs) for cytokine production, preserves the conventional dendritic cell (cDC) compartment, and accelerates antiviral CD8 T cell responses. Conversely, exogenous IFN-α administration in resistant animals ablates cDCs and delays CD8 T cell activation in the face of NK cell control of viral replication. Collectively, our data demonstrate that the ability of NK cells to respond very early to cytomegalovirus infection critically contributes to balance the intensity of other innate immune responses, which dampens early immunopathology and promotes optimal initiation of antiviral CD8 T cell responses. Thus, the extent to which NK cell responses benefit the host goes beyond their direct antiviral effects and extends to the prevention of innate cytokine shock and to the promotion of adaptive immunity.
Author Summary
To fight viral infections, vertebrates have developed a battery of innate and adaptive immune responses aimed at inhibiting viral replication or at killing infected cells. These responses include the early production of innate antiviral cytokines, especially interferons α and β (IFN-α/β), and the activation of cytotoxic lymphocytes such as the innate natural killer (NK) cells and the adaptive CD8 T cells. While critical for antiviral defense, cytokine or CD8 T cell responses can be detrimental or even fatal to the host when deregulated. Therefore, we need to better understand how the different arms of antiviral immunity are regulated. In particular, NK cells are proposed to play a protective role in a variety of viral infection in humans, but the underlying mechanisms remain poorly understood. Here, in a mouse model of cytomegalovirus infection, we demonstrate that NK cells prevent an excessive production of IFN-α/β and promote more efficient antiviral CD8 T cell responses. We thus show that NK cells can help promote health over disease during viral infections by regulating both innate and adaptive immune responses. It will be important to examine in humans whether NK cells control innate cytokine production to prevent immunopathology and to promote adaptive immunity against herpesviruses, HIV-1, influenza, or SARS.
doi:10.1371/journal.ppat.0030123
PMCID: PMC1950948  PMID: 17722980

Results 1-2 (2)