Molecular regulation of T cell responsiveness
4139, 4105 Wi Institute Medical Research
1111 Highland Ave
Madison, WI 53705
Immunology; Developmental Biology & Regenerative Medicine
Our work involves utilization of numerous murine models of T cell unresponsiveness and functional analysis of peripheral blood mononuclear cells from human subjects. CD25+ T regulatory (Treg) cells are a subset of CD4+ T cells with an anergic phenotype that suppress immune responses by a poorly understood mechanism. Treg cells develop in the thymus (thymically 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. Our studies suggest that GRAIL is expressed along a continuum in anergic T cells and suppressive T cells and exerts its effect through modulation of the actin cytoskeleton. Our 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 induction and function of CD25+ Treg cells, directed approaches can be developed for therapeutic alternatives to varied disease states that result from inappropriate immune responses.
A second line of investigation in our 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 regions 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. 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 our 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.