“Nothing in life is to be feared, it is only to be understood.
Now is the time to understand more, so that we may fear less.”
- Marie Curie
Research in our laboratory is focused on determining the phenotype, function, and specificity of T cells in neurological disorders.
Our overarching goal is to gain novel scientific knowledge in regard to adaptive immune responses in neurological diseases that will help guide clinical practice.
T Cell Repertoire in Autoimmunity
Multiple sclerosis (MS) is an incurable, chronic autoimmune disease of the central nervous system. A major component of MS pathogenesis is the autoimmune response of self-reactive T cells to myelin antigens. In MS, multiple central nervous system self-antigens are targets for T cells and the specificity of which is thought to fluctuate over time. Heterodimeric αβ T cell receptors expressed on T cells recognize peptides presented on human leukocyte antigens or major histocompatibility complexes. Heterodimeric TCRs expressed in each T cell are derived by a semi random recombination
event resulting in a hugely diverse TCR repertoire. A hallmark of antigen specific T cell response is the clonal expansion, with expanding T cells expressing identical TCR sequences. Therefore, the actual TCR sequences serve as a unique identifier of a T cell’s ancestry. To better understand the T cell response in neurological conditions, we develop and employ novel single-cell sequencing techniques to understand several key questions
in MS patients:
- What are the T cell repertoire and transcriptional profile in newly diagnosed patients
and their respective mouse models?
- What are the T cell repertoire and transcriptional changes in different disease states
and upon treatment?
- How does the dysregulated T cell response contribute to pathophysiology?
T Cell Specificity and Function in Autoimmunity
A long-standing question in MS is what triggers the disease. Recent development in TCR sequencing has enabled us to better understand the TCR repertoire in various disease settings at an unprecedented level. However, we lack tools to leverage TCR sequence information to determine their specificity. To better bridge TCR sequence information to its specificity, we and others have developed computational and high-throughput antigen discovery methods. These technologies enable us to ask several unanswered questions:
- What is the specificity of T cells in MS and other neurological diseases?
- How cross reactive are the T cells in autoimmune diseases?
- What is the dynamics of antigen-specific T cells in different disease states and upon treatment?
- Develop novel methods to determine T cell specificity
Systems Analysis of Adaptive Immunity in Neurological Disorders
Multiple sclerosis is a quintessential autoimmune neuroinflammatory disease. It is becoming more and more evident that inflammation and adaptive immune cells play a role in aging, neurodegenerative, and neuropsychiatric diseases. We have demonstrated an interaction of T cells and neural stem cells in aging and the role of T cells in Alzheimer’s disease. Highlighting the neuroimmune interactions in aging. By leveraging varied combinatorial single-cell technology approaches and systems level analysis of adaptive immunity in neurological conditions, we hope to address:
- What are the changes in the adaptive immunity in aging and neurodegenerative conditions in humans?
- How does chronic inflammatory immune responses contribute to central nervous system neurodegeneration?
- How do we correlate changing immune responses in neurodegeneration to imaging biomarkers?