Education and Training
1996 BS Furman University
2002 MS Emory University
2008 PhD Emory University
2008-2013 Postdoctoral training St Jude Children's Research Hospital
Main areas of research: (1) Neonatal Tolerance to Beta Cell antigens (2) Microbiota Specific T Cell Selection and 3) Chimeric Antigen Receptor (CAR) ITAM usage and functionality.
The foundation of my research centers around neonatal tolerance to organ specific antigens and microbiota. The mechanism by which this occurs is still unclear, however efficient deletion of highly reactive T cells specific for self-antigens and microflora are thought to occur, leaving a healthy immune homeostasis between low affinity self-reactive T cells and regulatory T cells. We have shown that when bone marrow derived antigen presenting cells (APCs) ectopically express a beta cells specific antigen (insulin), there are increased selection pressures on these insulin specific T cells resulting in increased negative selection and increased Regulatory T cell (Treg) development. Importantly mice that ectopically exposed to insulin antigens are protected from developing T1D using Non-Obese diabetic, spontaneous T1D mouse model. We are currently testing whether neonatal exposure to other pancreatic antigens (or the combination of antigens) can further strengthen central and peripheral tolerance in the NOD mouse models of T1D.
A second aspect of my research is focused on how early microflora exposure impacts thymocyte development of microflora specific T cells. Commensal bacteria are integral for immune homeostasis, however the impact of specific bacterium on T cell selection is underappreciated. We are investigating the role of specific microflora on the migration of gut antigen presenting cells (APCs) to the thymus and the cross talk that occurs between these gut derived APCs and thymocytes development. Of particular interest is how the timing of microflora exposure impacts the T cell repertoire, including gut residing regulatory T cells and subsequent gut homeostasis early compared to later exposure.
The last area of my research is focused on how to better achieve long lasting and functional Chimeric Antigen Receptors (CAR) T cells. Integral to both intracellular transduction of the TCR/CD3 complex and CARs are the Immunoreceptor Tyrosine-based Activation Motifs (ITAMs) in the recruitment and activation of adaptor molecules to carry forward and amplify the transduction signal. The aim of this work is to better understand the functionality of the CD3 zeta chains found in CARs by manipulation of the ITAM sequences and the consequences that these mutations may have on functionality and persistence of CD8+ CAR T cells in a CD19+ Tumor mouse model.
Major Projects in the Lab
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 suppression 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.