The immune system uses antigen receptors on T cells (TCRs) to detect antigens, such as peptides or glycolipids that are presented by antigen-presenting molecules present on the surface of antigen-presenting cells. The antigen presenting molecules, termed Major Histocompatibility proteins have evolved to present peptides, while the structurally related CD1 family has evolved to bind glycolipids that are bound in deep and hydrophobic binding grooves. Upon binding of the TCR to the MHC or CD1 bound antigen, the T cell becomes activated, leading to the production of cytokines, second messenger molecule, that activate other immune cells for a full immune response to counter an infection, in the case of foreign antigens. We have found that peptides can also be presented by CD1d, and that certain peptides can activate T cells that are considered specific for certain glycolipid antigens. Our lab uses Xray crystallography to investigate at the atomic level the binding of the antigen-receptor to the peptide antigen when presented by CD1d in order to understand the structural requirements for T cell activation. This knowledge will lead to the design of altered peptide ligands that can be selected to either enhance the immune response to infection or to change the cytokine profile, increased production of either pro- inflammatory or anti-inflammatory cytokines, to help ameliorate autoimmune diseases, such as diabetes or multiple sclerosis.

Public Health Relevance

The immune system can detect and respond to foreign peptide as well as glycolipid antigens. Specialized lymphocytes detect peptides when presented by antigen presenting molecules termed Major Histocompatibility proteins (MHC I and II), while glycolipids are presented by the structurally related CD1 family. However, certain peptides can also be recognized when presented by CD1d by T cells that generally only recognize lipid antigens. Understanding the structural basis of the recognition of those different antigens and the functional properties of the T cells is crucial for the future development of novel therapeutic to modulate the immune response.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Cellular and Molecular Immunology - A Study Section (CMIA)
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Leitner, Wolfgang W
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La Jolla Institute
La Jolla
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Zajonc, Dirk M (2016) The CD1 family: serving lipid antigens to T cells since the Mesozoic era. Immunogenetics 68:561-76
Girardi, Enrico; Wang, Jing; Zajonc, Dirk M (2016) Structure of an ?-Helical Peptide and Lipopeptide Bound to the Nonclassical Major Histocompatibility Complex (MHC) Class I Molecule CD1d. J Biol Chem 291:10677-83
Birkholz, Alysia M; Girardi, Enrico; Wingender, Gerhard et al. (2015) A Novel Glycolipid Antigen for NKT Cells That Preferentially Induces IFN-? Production. J Immunol 195:924-33
Birkholz, Alysia; Nem?ovi?, Marek; Yu, Esther Dawen et al. (2015) Lipid and Carbohydrate Modifications of ?-Galactosylceramide Differently Influence Mouse and Human Type I Natural Killer T Cell Activation. J Biol Chem 290:17206-17
Zajonc, Dirk M; Girardi, Enrico (2014) A ?? T-cell glimpse of glycolipids. Immunol Cell Biol 92:99-100