The long-term goal of our research is to expand our understanding of the following five areas: 1) The cellular and molecular events that influence allergic disease susceptibility and initiation; 2) The mechanisms regulating immunity to parasites as a foundation for vaccine development; 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 and infectious disease, 4) The role of group 2 innate lymphoid cell (ILC2) subsets in mucosal barrier immunity, and 5) 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. 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 cytometry in combination with conventional immunofluorescence (Figure 1) and live tissue imaging using multi-photon microscopy (Figure 2).
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 and function as well as 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 studies of Type-2 immunity into innate lymphoid cells, specifically ILC2s. Our most recent publication described the transcription factor, BATF, as being required for the migratory iILC2 subset which traffics to the lung early after helminth infection and produces type 2 cytokines important in tissue repair (http://immunology.sciencemag.org/cgi/content/full/5/43/eaay3994?ijkey=WjdGW8JiShChg&keytype=ref&siteid=immunology) (Figure 5). We are interested in further understanding where this migratory iILC2 subset originates, the mechanism of trafficking, and how it contributes to the long-term immune landscape of the lung. In addition to murine ILC2 studies, we are also investigating these cells in human lung tissue.
We are also very interested in anti-helminth immunity. Currently, the breadth, depth, and antigen-reactivity of the responding CD4+ T cell repertoire after helminth infection is largely unknown, and few studies to date have investigated in depth the responding T cell repertoire. How the anti-helminth T cell repertoire changes upon secondary infection, whether it differs among lymphoid and nonlymphoid tissues, and the uniqueness of the repertoire between Tfh and Th2 cell subsets remains unexplored. Our data suggest that the anti-helminth T cell repertoire is diverse and with broad antigen-specificity. This diversity makes the response to these large extracellular worms unique from what is observed in responses to dominant epitopes found in viral or bacterial immunity. It also complicates our understanding of vaccine epitope discovery. We hope to leverage a better understanding of the natural immune repertoire into the development of more effective and safe vaccine.
Another area we are excited about involves our efforts to understand IFN-gamma driven autoinflammatory diseases with the goal of modeling rare childhood syndromes. We have generated a new mouse model harboring a human mutation present in rare proteasome-associated autoinflammatory syndromes (PRAAS) (Figure 6). 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.
Lastly, we are exploring various mechanisms related to how early-life helminth exposure can prevent or ameliorate allergic disease symptoms (Figure 8). The goal is to uncover novel mechanisms that can be leveraged into therapies that mimic the beneficial effects of helminths on allergic disease susceptibility.
|Postdocs and Fellows:
|Mindy M Miller, PhD
I received my PhD from the University of Missouri where I investigated neonatal CD4 T cell responses under the guidance of Dr. Habib Zaghouani. This work introduced me to the concept that immune responses in early life can profoundly shape the development of diseases later on. Along these lines, in the Reinhardt Laboratory I am currently investigating how helminth infection imprints a protective function on macrophages to prevent or alleviate allergic asthma. In addition, my research has focused on the functional characterization of a novel subset of migratory ILC2 cells that are critical in early barrier immunity.
|Ivy K Brown, MSc (Sr. Researcher/Lab Manager)
I obtained my master’s degree in Molecular Biology specialized in human health at the Free University of Brussels in Belgium. My current research projects primarily focus on characterizing various mouse models of relevant human diseases, as well as various other projects in which the lab is invested. We aim to investigate the cellular mechanisms behind these disorders with an ultimate goal of developing therapies for treatment. I am also responsible for lab management and all the duties encompassed therein.
Postdocs and Fellows:
Thomas O’Brien (Beckman-Coulter)
Preeyam Patel (Postdoc New York University)
Katherine Bao (Postdoc Genentech)
Mark Dell’Aringa (Postdoc National Jewish Health)
Research Scientists/ Lab Managers:
Ann Miller (Duke University)
Julio Barrera (Duke University)
Jingxiao Jin (Baylor Medical School)
Simon Jiang (Duke University; Element Genomics)
Early Career Scientists/ Pre-collegiate Students:
Rebecca Shen (Stanford)
Reinhardt Lab (Winter 2020)
Lee, Otto and Mindy – Science Immunology publication commemoration!
Reinhardt Lab (Winter 2019)
Lee, Ivy and Mindy – Happy holidays!
Reinhardt Lab (Summer 2019)
Mindy, Mary, Ivy and Lee - Winners of the annual retreat costume contest!
Reinhardt Lab (Summer 2018)
Mindy, Ivy, and Mary on Independence Day
Reinhardt Lab (Winter 2017)
Mark, Preeyam, and Ivy - Welcome to Denver!
Reinhardt Lab (Winter 2014)
Tommy, Mark, Katherine, Jingxiao and Ann (not pictured) –
The Fantastic First Five
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