NIH Training Grant Fellow: Christie Mortales

Christie Mortales

            Christie Mortales earned her B.S. in Cellular, Molecular, and Developmental Biology at the University of Washington in Seattle in 2010.  Before coming to UCI to pursue her graduate studies, she worked for two years at the Fred Hutchinson Cancer Research Center in Seattle as a research technician in Dr. Edus Warren’s lab in the Program in Immunology, Clinical Research Division.  Her primary focus was on examining how engineered cytotoxic T cells targeted and killed tumor cells that expressed specific antigens, giving insight into the better development of T cell immunotherapies for cancer patients.

            Christie has always kept a strong interest in the field of immunology, which was what brought her to UCI.  As part of Dr. Michael Demetriou’s lab in the Department of Microbiology and Molecular Genetics, she has now begun to delve into an exciting and unconventional aspect of the field, which is how surface protein glycosylation dynamically determine the course of development and alter the function of immune cells.  With close guidance from Dr. Demetriou, Christie has independently developed a thesis project on dissecting how Asn (N)-glycosylation regulates the antigen presenting function of B cells and their interactions with CD4 T helper (Th) cells. 

            Dysregulation of N-glycan biosynthesis plays a critical role in the pathogenesis of autoimmunity in mice and humans.  Most cell surface proteins are modified by the addition of Asn (N)-linked glycans in the endoplasmic reticulum, with further modifications occurring in the Golgi apparatus.  In the Golgi, N-acetylglucosaminyltransferase enzymes (Mgat1, Mgat2, Mgat4a/b, and Mgat5) act sequentially to transfer N-acetylglucosamine (GlcNAc) from the substrate UDP-GlcNAc onto N-glycan intermediates.  Cell surface receptors bind multi-valent galectins via their attached N-glycans, forming a molecular lattice that regulates protein membrane localization and surface loss to endocytosis.  To date, little is known about how N-glycosylation affects the APC function of B cells.

            B cells can act as antigen presenting cells (APCs), which activate naïve CD4 Th cells and influence Th differentiation into effector types that mediate cellular (Th1, Th17), humoral (Th2), or suppressive (Treg) immune responses.  Her early data suggests N-glycan deficiency on B cells results in higher levels of surface receptors that, upon B cell activation, enhance intracellular signaling to promote APC co-stimulation which drive CD4 Th differentiation into Th1 cells.  This has implications in the context of T cell mediated autoimmune diseases such as multiple sclerosis (MS), where Th1/Th17 cells are major players.  Thus, Christie’s project will elucidate a novel mechanism of how N-glycosylation influences the APC function of B cells to modulate the Th cell effector response, and how that may potentiate autoimmunity.  Her project will also be extended to look at the other APCs (dendritic cells and macrophages) to see whether N-glycan deficiency affects their function, interaction with T cells, and role in autoimmunity.

 

Publications:

  1. Jeffrey Chou, Matthew P Fitzgibbon, Christie-Lynn L. Mortales, Andrea M. H. Towlerton, Melissa P Upton, Raymond S Yeung, Martin W McIntoshm, and Edus H. Warren. “Phenotypic and transcriptional fidelity of patient-derived colon cancer xenografts in immune-deficient mice.” PLOS ONE 2013 Nov 20;8(11):e79874
  2. Jeffrey Chou, Lilien Voong, Christie L. Mortales, Andrea M. H. Towlerton, Seth M. Pollack, Xiaoji Chen, Cassian Yee, Paul F. Robbins, and Edus H. Warren. “Epigenetic modulation to enable antigen-specific T cell therapy of colorectal cancer.” Journal of Immunotherapy 2012 Feb-Mar;35(2):131-41

 

Honors and Awards:

2013-2014    NIH NIAID T32 Immunology Research Training Program (5T32 AI 060573), UC Irvine

April 2014     National Science Foundation Graduate Research Fellowship Program Honorable Mentions

May 2009      Office of Minority Affairs, Equal Opportunities Program Endowed Scholarship, Bank of America Recognition Award; University of Washington, Seattle, WA

Nov. 2008      Annual Biomedical Research Conference for Minority Students (ABRCMS) Outstanding Poster Presentation Award; Orlando, FL