The long-term goal of our research is to expand our understanding of the following: 1) The cellular and molecular events that influence allergic disease susceptibility and initiation; 2) The mechanisms regulating immunity to parasites; 3) The role and relationship between follicular T helper (Tfh), T-helper 2 (Th2), and follicular regulatory (Tfr) cells in the development/suppression of allergic disease and germinal center-derived lymphomas, and 4) The mechanisms driving interferon-mediated autoinflammatory diseases.
Our work has largely focused on understanding the generation, function, and cell fate decisions of CD4+ T-helper (Th) cell subsets in vivo following infection with various pathogens. To do this, we make use of various cytokine and transcription factor reporter mouse models to elucidate Th1, Th2, Tfh, and Tfr development and function. These models provide the opportunity to visualize immune cell function directly in vivo using flow cytometery in combination with conventional immunofluorescence (Figure 1) and live tissue imaging using multi-photon microscopy (Figure 2).
In addition, we have continued to develop second-generation cytokine and transcription factor reporter systems to address unanswered questions in allergic inflammation, CD4 T cell biology, and cytokine regulation (Figure 3).
Together, these studies have provided the basis to understand an unexpected, yet important bifurcation in type-2 immunity orchestrated by follicular T cells in the lymphoid tissues and Th2 cells in mucosal non-lymphoid tissues (Figure 4).
Beyond visualizing cellular function, these reporter animals provide excellent tools to study gene expression, gene function, and epigenetic gene regulation in physiologic settings. Specifically, these reporter systems allow us to isolate rare populations of innate and adaptive immune cells from various tissues to explore their transcriptional programs and epigenetic profiles at various times during an immune response. We have now established collaborations to continue to investigate these cellular programs and epigenetic events at the single cell level.
We have recently expanded our focus to explore three new areas.
First, we are interested in understanding the relationship between Tfh cells and Tfr cells in chronic parasitic infections and during the development and progression of B cell lymphomas (Fig. 5).
Second, we have expanded our research in IFN-gamma driven autoinflammatory diseases (Figure 6) to look at rare childhood syndromes. We have generated a new mouse model harboring a human mutation present in rare proteasome-associated autoinflammatory syndromes (PRAAS). This is the first PRAAS-specific mouse model, and this pre-clinical model will allow us to better understand how type-1 and type-2 interferons are involved in disease pathogenesis. We believe mutations in subunits of the immunoproteasome create a pathogenic feedback loop where chronic production of IFNs promote increased inflammation and pathology.
Third, we are exploring various mechanisms related to how early-life
helminth exposure can prevent or ameliorate allergic disease symptoms (Figure 6).
The goal is to uncover novel mechanisms that can be leveraged into therapies
that mimic the beneficial effects of helminths on allergic disease