RESEARCH

Currently funded projects are aimed at elucidating parameters of beta cell antigen specific T cell development, mechanisms important for tolerance induction to intestinal microbes, and cross talk between the gut and thymus in adults and neonates. Other areas of interest include understanding the role of ITAM diversity in CAR-T cell function and persistence. 

Project 1: Understanding central tolerance mechanisms and their dysregulation in autoimmunity- Funded by NIDDK R01.

Our early work on autoimmune T cell development has led to the discovery that ectopic expression of insulin (InsB9-23) within insulin specific TCR retrogenic mice stops autoimmune diabetes through the generation of Treg development and not through negative selection (J. Immunology 2017). Additionally, we have shown mutating a critical insulin epitope (InsY16A) impacts thymic development of insulin specific Tregs, highlighting the role of the Ins9-23 epitope in central and peripheral tolerance (Diabetes 2020). More recent work is focused on the role of CD207 (Langerin+) and CX3CR1+ antigen presenting cells in neonatal tolerance and Foxp3+ Regulatory T cell (Treg) development.  In order to better understand antigen specific Treg development in vivo, we have developed a novel mouse model that combines temporally induced, tissue specific OVA antigen expression with a Ca+ biosensor. With this mouse model, our goal is to determine the relationship between antigen availability with particular APCs, TCR signal strength and Foxp3 expression during thymocyte development and central tolerance.  The long-term goal of this research program is to identify the underlying issues in the breakdown in tolerance to self, which may be applicable in establishing peripheral tolerance to antigen specific autoimmune T cells.  

Project 2: Microbiota Specific T Cell Selection- Funded by NIAID R01.

It remains unclear how tolerance against the microbiota is achieved, and further, if the ability to induce tolerance to intestinal microbes is limited to a specific early life developmental window. Using a mouse model whose T cell receptor recognizes intestinal microbes, we find intestinal colonization with this microbe leads to selection of T cells specific for that organism. We hypothesize that intestinal antigen presenting cells (APCs) that encounter these organisms traffic to the thymus where they induce T cell selection. Aim 1:  Define whether there are differential impacts on T cell development depending on the developmental window of when microbial colonization occurs. We will further define if timing of colonization with select microbes promotes or limits development of inflammatory and/or autoimmune disease. Aim 2: Define how the microbe or microbial product travels from the intestine to the thymus. We will determine the intestinal cell population required for trafficking of this microbe as well as define transcriptional profiles that allow for T cell selection. This will identify pathways that we will be able to manipulate to limit or rescue from the development of autoimmunity. 

Project 3: The role of ITAM Diversity in Chimeric Antigen Receptor (CAR) T cell function and persistence.

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 humans and mouse CAR T cells by manipulation of the ITAM sequences and the consequences that these mutations may have on functionality and persistence of CD4+ and CD8+ CAR T cells.

Graduate Student projects are available for all 3 areas of my Research Program: 1) Self-Reactive T Cell Development in Type 1 Diabetes 2) Microbiota Specific T Cell Selection and 3) Chimeric Antigen Receptor (CAR) ITAM usage and functionality.

Matt Bettini
Matt Bettini, PhD
Assosciate Professor
Microbiology & Immunology

CONTACT US

Department of Pathology
Division of Microbiology and Immunology
University of Utah
Emma Eccles Jones Medical Research Building
15 N. Medical Drive East, Rm 1830A
Salt Lake City, UT 84112
email: matt.bettini@path.utah.edu
phone: 801-213-8560