Associate Professor of Microbiology and Immunology
Autoimmunity, Central Tolerance, Thymic Development, Tolerance to Microbiota, Chimeric Antigen Receptors (CARs)
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.
I am currently accepting Graduate Students for the following R01 funded projects: 1) Investigating the role of early exposure to microflora in central tolerance and its impact on Type 1 Diabetes. 2) Neonatal tolerance to pancreatic antigens by targeting thymic and peripheral DCs
- Lin Y, Perovanovic J, Kong Y, Igyarto BZ, Zurawski S, Tantin D, Zurawski G, Bettini M, Bettini ML (2022 May 27) Antibody-Mediated Targeting of a Hybrid-Insulin-Peptide Towards Neonatal Thymic Langerin+ Cells Enhances T Cell Central Tolerance and Delays Autoimmune Diabetes. Diabetes, db211069. doi: 10.2337/db21-1069. Online ahead of print.PMID: 35622068
- Zegarra-Ruiz DF, Kim DV, Norwood K, Kim M, Wu WH, Saldana-Morales FB, Hill AA, Majumdar S, Orozco S, Bell R, Round JL, Longman RS, Egawa T, Bettini ML*, Diehl GE* (2021 Jun) Thymic development of gut-microbiota-specific T cells. Nature, 594(7863):413-417. doi: 10.1038/s41586-021-03531-1. Epub 2021 May 12.PMID: 33981034 *Co-Corresponding Author
- Diabetes, 69(3):392-400. doi: 10.2337/db19-0821. Epub 2019 Dec 13. PubMed PMID: 31836691; PubMed Central PMCID: PMC7034183. A Critical Insulin TCR Contact Residue Selects High-Affinity and Pathogenic Insulin-Specific T Cells.
- Kim M, Galan C, Hill AA, Wu WJ, Fehlner-Peach H, Song HW, Schady D, Bettini ML, Simpson KW, Longman RS, Littman DR, Diehl GE (2018 Jul 17) Critical Role for the Microbiota in CX3CR1+ Intestinal Mononuclear Phagocyte Regulation of Intestinal T Cell Responses. Immunity, 49(1):151-163.e5. doi: 10.1016/j.immuni.2018.05.009. Epub 2018 Jul 3. PMID: 29980437; PMC6051886.
- Lee T, Sprouse ML, Banerjee P, Bettini, Bettini ML (2017). Ectopic Expression of Self-Antigen Drives Regulatory T Cell Development and Not Deletion of Autoimmune T Cells. J Immunol, 199(7), 2270-2278.
- Bettini ML, Chou PC, Guy CS, Lee T, Vignali KM, Vignali DAA (2017 Sep 1). Cutting Edge: CD3 ITAM Diversity Is Required for Optimal TCR Signaling and Thymocyte Development. J Immunol, 199(5), 1555-1560.
- Lee T, Shevchenko I, Sprouse ML, Bettini, Bettini ML (2016 Jul 11). Retroviral Transduction of Bone Marrow Progenitor Cells to Generate T-cell Receptor Retrogenic Mice.LID - 10.3791/54196 [doi]. J Vis Exp, (113).
- Bettini ML, Guy C, Dash P, Vignali KM, Hamm DE, Dobbins J, Gagnon E, Thomas PG, Wucherpfennig KW, Vignali DA (2014). Membrane association of the CD3epsilon signaling domain is required for optimal T cell development and function. J Immunol, 193(1), 258-67.
- Bettini ML, Bettini, Nakayama M, Guy CS, Vignali DA (2013 Oct). Generation of T cell receptor-retrogenic mice: improved retroviral-mediated stem cell gene transfer. Nat Protoc, 8(10), 1837-40.
- Bettini ML, Pan F, Bettini, Finkelstein D, Rehg JE, Floess S, Bell BD, Ziegler SF, Huehn J, Pardoll DM, Vignali DA (2012 May 25). Loss of epigenetic modification driven by the Foxp3 transcription factor leads to regulatory T cell insufficiency. Immunity, 36(5), 717-30.