The foundation of my research centers around neonatal tolerance to organ specific antigens and microbiota. It has been shown that there is a neonatal window of opportunity in which the immune system can develop tolerance to microflora as well as self-antigens. 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.
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 CAR T cells. The TCR/CD3 complex allows for extracellular stimuli to fine tune intracellular signaling that allows for differential T cell responses that include survival, proliferation, activation, effector functions and death. Integral to the intracellular transduction of the TCR/CD3 complex and CARs are the Immunoreceptor Tyrosine-based Activation Motifs (ITAM) in the recruitment and activation of adaptor molecules to carry forward and amplify the transduction signal. The aim of this project 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.