Margarita Dominguez-Villar is an Associate Research Scientist in the Department of Neurology at Yale School of Medicine. She graduated magna cum laude in 2000 from the University of Granada (Spain) with a degree in biochemistry and molecular biology, and she obtained her PhD from the University of Cadiz, Spain, in 2007.
During her PhD, she studied the molecular mechanisms of peripheral tolerance in hepatitis C infection. After a short post-doctoral period at Karolinska Institute, Sweden, under the supervision of Dr Benedict J Chambers, she joined Dr David Hafler's laboratory at Harvard Medical School in January 2009 as a post-doctoral associate to work on regulatory T-cell function in human autoimmune diseases.
In 2010, Dr Dominguez-Villar moved to Yale University with Dr Hafler, and in 2012, she became a member of the junior faculty at Yale School of Medicine. Her research goals focus on understanding how regulatory T cells and effector T cells function in patients with multiple sclerosis, in order to ultimately design therapeutic strategies that restore the deficient immune suppression and eliminate autoantigen-specific effector T cells present in patients with the disease.
Molecular mechanisms underlying regulatory T-cell dysfunction in multiple sclerosis
Foxp3+ regulatory T cells (Tregs) are critical to maintain peripheral tolerance and have a central role in preventing autoimmune responses in both murine models of autoimmunity and in humans.
We have recently found that patients with relapsing–remitting multiple sclerosis (MS) have an increased frequency of Th1-type, IFNγ-secreting Tregs compared to healthy controls, associated with loss of in vitro suppressor function. This type of Treg has also been found to be increased in patients with type 1 diabetes, which suggests that this reprogramming can be a common mechanism in autoimmune diseases and reflects genetic and epigenetic defects that lead to the dysregulation of otherwise physiological mechanisms of Treg plasticity necessary to control inflammatory responses and prevent autoimmunity.
Thus, it is a fundamental question to determine the mechanisms that generate Th1-Tregs in autoimmune diseases and how these cells function in vivo and in vitro under basal, inflammatory, and therapeutic conditions in order to ultimately design new therapeutic interventions that restore their suppressive ability in these settings.
This study will test the hypothesis that the immune environment dictates the pathway of Treg differentiation in humans, and that these processes are altered in individuals with MS. The hypothesis will be tested by determining the molecular pathways that differentiate Th1-Treg subsets in patients with MS and how these pathways can be modulated to re-acquire Treg functionality. It is hoped that the identification of the transcriptional mechanisms that generate Th1-Tregs in MS and characterization of how these cells dysfunction in vivo will ultimately lead to the design of new therapeutic interventions that restore their suppressive ability in patients with MS.
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