Over the past 10 years, a tremendous amount of data has accumulated, which demonstrates the role of glycolipid-reactive T cells in autoimmune disease, host defense and tumor development. T cells and NKT cells can respond to a broad pool of self and foreign antigens presented by CD1 molecules and can trigger killing of the antigen presenting cell, through cytotoxic T lymphocytes (CTLs), or recruit help (T helper cells) from the humoral immune system through production of soluble antibodies. Our lab is interested in the molecular mechanisms of lipid antigen recognition in cell-mediated immunity. Toward this goal, we determine the binding kinetics of various glycolipid- reactive T cell receptor's (TCR's) with various CD1 antigen-presenting molecules by surface plasmon resonance studies (SPR). We will further correlate the obtained results with data obtained by measuring cytokine production upon T cell activation using T cell hybridomas. Ultimately we propose to determine the three-dimensional structure of CD1 antigen receptors in complex with different lipids and cognate T cell receptors (TCR's) by x-ray crystallography. We specifically address the following specific aims: 1) What are the biochemical and functional properties of human and mouse sulfatide-reactive NKT cells. We will determine the structure of sulfatide loaded human CD1a and mouse CD1d in complex with the respective TCR and characterize their binding kinetics by SPR. Comparisons of both complexes will provide insights into the similarities and disparities of sulfatide recognition by the immune system and will shed light on the molecular mechanism of their activation. 2) We will structurally and functionally characterize differences in glycolipid recognition of Borrelia burgdorferi glycolipids by human and mouse NKT cells. 3) We will characterize binding of novel endogenous self-lipids to mouse CD1d and their recognition by NKT cells. Structural insights into the differences of self vs. microbial antigen presentation will help understand the role of microbial lipids and lipid-reactive T cells in host defense and autoimmune diseases. Public Health Relevance: NKT cells are specialized lymphocytes that consist of several subtypes and can respond to glycolipids from infectious organisms, such as Borrelia burgdorferi the causative agent of Lyme disease and self-lipids, during the course of autoimmune disease such as Multiple sclerosis. Understanding the functional properties of these cell types at a molecular level is crucial for the future development of novel chemotherapeutic agents or adjuvants to combat both diseases.

Public Health Relevance

NKT cells are specialized lymphocytes that consist of several subtypes and can respond to glycolipids from infectious organisms, such as Borrelia burgdorferi the causative agent of Lyme disease and self-lipids, during the course of autoimmune disease such as Multiple sclerosis. Understanding the functional properties of these cell types at a molecular level is cruical for the future development of novel chemotherapeutic agents or adjuvants to combat both diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI074952-04
Application #
8214630
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Miller, Lara R
Project Start
2009-03-01
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
4
Fiscal Year
2012
Total Cost
$403,557
Indirect Cost
$183,034
Name
La Jolla Institute
Department
Type
DUNS #
603880287
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Maricic, Igor; Girardi, Enrico; Zajonc, Dirk M et al. (2014) Recognition of lysophosphatidylcholine by type II NKT cells and protection from an inflammatory liver disease. J Immunol 193:4580-9
Zajonc, Dirk M; Girardi, Enrico (2014) A ýýýý T-cell glimpse of glycolipids. Immunol Cell Biol 92:99-100
Aspeslagh, Sandrine; Nemcovic, Marek; Pauwels, Nora et al. (2013) Enhanced TCR footprint by a novel glycolipid increases NKT-dependent tumor protection. J Immunol 191:2916-25
Girardi, Enrico; Yu, Esther Dawen; Li, Yali et al. (2011) Unique interplay between sugar and lipid in determining the antigenic potency of bacterial antigens for NKT cells. PLoS Biol 9:e1001189
Joyce, Sebastian; Girardi, Enrico; Zajonc, Dirk M (2011) NKT cell ligand recognition logic: molecular basis for a synaptic duet and transmission of inflammatory effectors. J Immunol 187:1081-9
Yu, Esther Dawen; Girardi, Enrico; Wang, Jing et al. (2011) Cutting Edge: Structural basis for the recognition of ýý-linked glycolipid antigens by invariant NKT cells. J Immunol 187:2079-83
Aspeslagh, Sandrine; Li, Yali; Yu, Esther Dawen et al. (2011) Galactose-modified iNKT cell agonists stabilized by an induced fit of CD1d prevent tumour metastasis. EMBO J 30:2294-305
Dieude, Melanie; Striegl, Harald; Tyznik, Aaron J et al. (2011) Cardiolipin binds to CD1d and stimulates CD1d-restricted ýýýý T cells in the normal murine repertoire. J Immunol 186:4771-81
Pauwels, Nora; Aspeslagh, Sandrine; Vanhoenacker, Gerd et al. (2011) Divergent synthetic approach to 6''-modified ?-GalCer analogues. Org Biomol Chem 9:8413-21
Wang, Jing; Li, Yali; Kinjo, Yuki et al. (2010) Lipid binding orientation within CD1d affects recognition of Borrelia burgorferi antigens by NKT cells. Proc Natl Acad Sci U S A 107:1535-40

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