My research laboratory has had a longstanding interest in the cellular and molecular mechanisms that modify immune responses. My work involves utilization of numerous murine models of T cell unresponsiveness and functional analysis of peripheral blood mononuclear cells from human subjects with a particular interest in allergic inflammation and the contexts that lead to its development. Inspired by our observations that T regulatory (Treg) cells are important during in vivo T cell unresponsiveness in murine models, we turned to human disease states that are the result of imbalanced T cell responses. Our study population is infants and children since the foundation for allergic disease is established early in life.
CD25+ Treg cells are a subset of regulatory T cells with an anergic phenotype that suppress immune responses in an antigen-specific fashion by a poorly understood mechanism. Treg cells develop in the thymus (naturally occurring) or in lymphoid tissue (induced). Ongoing work in my laboratory has demonstrated a link between GRAIL (RNF128), an anergy-related E3 ubiquitin ligase, and CD25+ Treg cells. We hypothesize that GRAIL is necessary for the optimal function of naturally occurring and induced CD25+ Treg cells. My laboratory has recently developed a novel conditional knockout mouse model to assist with characterizing the role of GRAIL in Treg cell biology and various immune responses. By understanding the molecular basis for suppressor function of CD25+ Treg cells, directed approaches can be developed for therapeutic alternatives to varied disease states that result from inappropriate adaptive immune responses.
A second line of investigation in my laboratory involves translational research with infants that are protected from developing allergic disease secondary to unique, but poorly defined environmental exposures. Farming environments have been found to be protective against the development of allergic diseases on multiple continents and include epidemiologic findings from the dairy farming region of Wisconsin. Allergic diseases are major public health problems in children and adults and are initiated in early childhood by poorly understood mechanisms that include alterations in immune maturation and association with severe viral respiratory infections. Mouse models of allergic disease strongly implicate a role for CD25+ Treg cells in initiation, perpetuation and regulation of allergic inflammation. Accumulating published data demonstrates critical interactions between the adaptive and innate immune system impact the development of allergic sensitization and clearance of common respiratory viral infections. The goals of our currently funded study are focused on in-depth investigations to better define the immunologic and environmental profiles at the inception of allergic diseases. Two aims of this study seek to interrogate innate immune cell function using an innovative and sensitive approach optimized in my research laboratory along with cutting-edge techniques to quantify Treg cell function. Results from this study will lead to a better understanding of the impact of farming environments on immune maturation and immune responses that protect against the development of allergic disease and significant respiratory viral infections. The long-term goal is to bring the farm "protective" factors to all infants in a primary prevention manner that would promote healthy immune maturation and overall improved health.