This proposal details a five year training plan for the development of a research program focused on the biology of invariant natural killer T (iNKT) cells and lipid antigens for these cells. iNKT cells are a subset of innate-like T cells that play n important role in host defense, allergic disease, autoimmunity, and cancer. While most T cells recognize peptide antigens, iNKT cells recognize lipid antigens. The lipid antigens recognized by iNKT cells are not well understood, and are of significant interest to the immunology community. The candidate recently provided a major step forward in the field by identifying beta-glucosylceramide (beta-GlcCer) as a potent self antigen for iNKT cells. Interestingly, in addition to being a self antigen, beta-GlcCer is also found in the human diet, and the candidate has identified dietary forms of beta-GlcCer that activate iNKT cells. Many structural variations of beta-GlcCer exist both in mammals and in the human diet. For both self and dietary lipid sources, the ability of individual beta-GlcCer variants to activate iNKT cells depends on their fin structural details. The goals of the proposed research are 1) to investigate the structural requirements for beta-GlcCer activity as an iNKT cell lipid antigen, 2) to determine how beta-GlcCer levels and beta-GlcCer structure are regulated in disease, and 3) to determine the functional role of beta-GlcCer as a dietary lipid antigen by assessing its subsequent effects on microbial defense. Since iNKT cells play an important role in diverse disease processes, the implications of this work to human disease are far-reaching. In addition to the proposed experiments, the candidate's career development goals are to gain further experience with lipid chemistry, experimental design, scientific communication, and the immunologic mechanisms of disease. A specific career development plan is described by both the mentor and candidate. The mentor, Dr. Michael Brenner, is very well established in the field of study, and has a strong training record. The candidate's long-term career goal is to attain a tenure-track faculty position and to continue his research on iNKT cells, lipid antigens, and the effects of diet on immunity.
Our studies aim to identify lipids that are normally present in the human body and lipids that are present in the diet that can activate the immune system. Identifying and understanding how these lipids activate the immune system are important to understand how we fight infection and how foods affect our immune system.
|Brennan, Patrick J; Cheng, Tan-Yun; Pellicci, Daniel G et al. (2017) Structural determination of lipid antigens captured at the CD1d-T-cell receptor interface. Proc Natl Acad Sci U S A 114:8348-8353|
|Clancy-Thompson, Eleanor; Chen, Gui Zhen; Tyler, Paul M et al. (2017) Monoclonal Invariant NKT (iNKT) Cell Mice Reveal a Role for Both Tissue of Origin and the TCR in Development of iNKT Functional Subsets. J Immunol 199:159-171|
|Kohlgruber, Ayano C; Donado, Carlos A; LaMarche, Nelson M et al. (2016) Activation strategies for invariant natural killer T cells. Immunogenetics 68:649-63|
|Kim, Edy Y; Lynch, Lydia; Brennan, Patrick J et al. (2015) The transcriptional programs of iNKT cells. Semin Immunol 27:26-32|
|Lynch, Lydia; Michelet, Xavier; Zhang, Sai et al. (2015) Regulatory iNKT cells lack expression of the transcription factor PLZF and control the homeostasis of T(reg) cells and macrophages in adipose tissue. Nat Immunol 16:85-95|
|Brennan, Patrick J; Tatituri, Raju V V; Heiss, Christian et al. (2014) Activation of iNKT cells by a distinct constituent of the endogenous glucosylceramide fraction. Proc Natl Acad Sci U S A 111:13433-8|