My laboratory is broadly interested in innate immunity, focused in three main areas:

Innate lymphoid cells (ILCs) in mucosal immunity

The laboratory has a long-standing interest in ILCs, which are lymphocytes that lack specific antigen receptors. They are found in the mucosae and mucosal-associated lymphoid tissues, where they promptly initiate cytokine responses to pathogens. In 2008, we identified a subset of ILCs that produce IL-22 in response to IL-23 in humans and mice [1]. These cells, which are now known as ILC3s, are a critical component of mucosal immune responses in health and disease. We then identified a second subset of mucosal ILCs, now known as ILC1, which uniquely reside at the intraepithelial interface, produce IFN-γ and are likely to play an important role in gastrointestinal immune responses [2]. We have profiled the transcriptome and the epigenome of ILCs in collaboration with the ImmGen consortium and the laboratory of Dr. Gene Oltz [3, 4]. We are investigating the role of transcription factors, such as the aryl hydrocarbon receptor (AHR) [5], in ILC development and the function of ILC surface receptors [6]. We are generating mouse models lacking ILC subsets to understand their functions during infection and inflammatory bowel disease.

Innate immune mechanisms in Alzheimer’s disease and neurodegeneration

Triggering receptors expressed on myeloid cells (TREM) are cell surface receptors encoded on human chromosome 6 that we found to be differentially expressed on granulocytes, dendritic cells, monocytes and tissue macrophages, including bone osteoclasts and brain microglia [7]. Humans lacking TREM2 or its associated signaling adaptor DAP12 develop a progressive, early onset dementia known as Nasu-Hakola disease. Recently, the TREM2 polymorphism R47H was implicated as a genetic risk for Alzheimer’s disease (AD). We are currently exploring the capacity of TREM2 to promote microglial cell function and how TREM2 allelic variants result in susceptibility to AD [8, 9]. We have also demonstrated that the cytokine IL-34 promotes the proliferation and survival of microglia through the receptor CSF-1R [10] and are testing IL-34 as a therapeutic target for neurodegenerative diseases

Plasmacytoid dendritic cells and IFNα/β in host defense and autoimmunity

Plasmacytoid dendritic cells (pDCs) are bone marrow-derived leukocytes that detect RNA and DNA from viruses and RNA/DNA/immunocomplexes through two endosomal sensors, TLR7 and TLR9, and secrete large amounts of type I interferons, i.e. IFNα/β. We described pDCs in 1999 as professional IFNα/β-producing cells that respond to influenza virus in human blood [11] and have contributed numerous milestones to the field of pDC research. We developed a transgenic mouse model in which pDCs can be specifically ablated for long periods of time [12]. By using this tool, we have assessed the relevance of pDCs  with respect to other anti-viral mechanisms during infection. Because autoimmune diseases, such as systemic lupus erythematosus (SLE), are associated with excessive pDC activation and secretion of IFNα, we are also exploring the impact of pDCs on models of SLE to determine whether disabling pDCs is a viable therapeutic strategy that can be applied to human autoimmune diseases.