Maria Bettini
Education and Training
2001 BS East Tennessee State University
2006 PhD Emory University
2006-2008 Postdoctoral training Emory University
2008-2013 Postdoctoral training St Jude Children's Research Hospital
Research Interests
T cell responses in autoimmunity develop under a unique set of conditions: relatively low TCR affinity, lack of danger signals, and chronic antigen stimulation. We are trying to understand how autoimmune T cells and suppressive regulatory T cells navigate these conditions to persist or fail.
Members of my laboratory utilize genetically modified mouse models, multi-color flow cytometry, single cell transcriptomics and epigenetic profiling to study autoimmune and regulatory T cell function. Most recently we began investigating the role of cholesterol metabolism in T cell function and its regulation by microbiota.
We have made several key observations regarding the function of Foxp3+ T cells in the context of autoimmune type 1 diabetes. Foxp3+ regulatory T cells employ multiple mechanisms to maintain immune and metabolic homeostasis, suppress autoimmunity, and aid in tissue repair. T cell receptor signaling guides Treg functions in the tissue. Current work in the lab is focused on leveraging our knowledge of basic cellular functions to improve Treg-based therapies. Our approaches include
(1) optimization of T cell receptors for effective TCR-redirected Treg therapy, (2) modification of Treg metabolism to improve Treg function, (3) and epigenetic remodeling to improve Treg survival. Additional projects are focused on transcriptional and epigenetic mechanisms that regulate autoimmune T cell function, autoimmune T cell memory, and T cell exhaustion in chronic inflammation.
Current ongoing projects
T cell receptor activation and control of regulatory T cell function
Regulatory T cells (Tregs) exhibit a unique T cell receptor (TCR) repertoire and enhanced TCR signaling in vivo compared to conventional T cells. We are applying high-throughput TCR sequencing, expression of select TCRs in vivo, and high resolution microscopy to investigate unique characteristics of Treg-derived TCRs and their cell-intrinsic differences in downstream signaling.
Image by Yi Jing - dSTORM microcopy image of an activated T cell's TCR clustering
Suppressive mechanisms of Foxp3+ regulatory T cells in autoimmune diabetes
Tregs exhibit a number of suppressive functions, including secretion of immune suppressive and tissue repair molecules. We are investigating Treg functional sub-populations in autoimmune environment, signals that drive their functional specialization, and the role of these molecules in regulation of pancreatic autoimmunity.
Image created with BioRender.com
TCR-redirected regulatory T cell adoptive therapy
We are testing natural and mutated TCRs for their ability to recruit Tregs into the autoimmune tissue and impart optimal function on TCR-redirected Tregs.
Image by Yi Jing - CD4+ T cells (green) infiltrating pancreatic islet and targeting insulin-producing beta cells (magenta).
Mechanisms that control T cell persistence in autoimmune tissue
Autoimmune T cells appear to avoid negative regulation by inhibitory receptors to maintain function long-term and avoid T cell exhaustion. We are applying single cell transcriptomics, epigenetics, and in vivo models to determine the mechanisms important for long-term maintenance of autoimmune T cells.
Image by Denise Allard Trout - Single cell RNAseq analysis of tissue-infiltrating CD4+ T cells.