CD1 presentation of self glycolipids and lipopeptides to T cells T cells that recognize autoantigens play a central role in psoriasis, thyroiditis, diabetes, multiple sclerosis, rheumatoid arthritis and other human autoimmune diseases. For many years all autoantigens for T cells were thought to be peptides bound to MHC proteins. However, new evidence shows that cellular lipids activated T cells when bound to CD1 proteins expressed on Langerhans cells and other dendritic cells. Recent studies show that CD1 and lipid autoreactive T cells occur frequently in individuals, such that they can now be considered a normal part of human immune responses. In particular, CD1a activates T cells that make IL-22, a cytokine that contributes to psoriasis. Whereas nearly all prior study of T cell autoantigens have focused on peptides, these findings considerably broaden the spectrum of autoantigens to include a variety of cellular lipids. Discovery of CD1 autoreactive T cells opens up a new and general pathway for discovering autoantigens that contribute to autoimmune disease and the use of lipids to treat autoimmune diseases. Whereas mouse models provide important information about in vivo function, tissue antigens and CD1-mediated T cell responses differ between mouse and human systems. Therefore, this proposal uses human tissues from normal donors and autoimmune disease patients to isolate new antigens and new T cell types. Specifically, experiments will use mass spectrometry to broadly measure the mass and chemical properties of lipids bound to human CD1a, CD1b and CD1c proteins. From this large pool of candidate autoantigens, lipids that lead to the strongest T cell activation will be identifed using T cell clones and polyclonal T cells from patients. After isolating antigenic compounds from tissues by liquid chromatography, their molecular structures will be solved by mass spectrometry. CD1 proteins and antigens will be used to measure T cell responses in normal donors and patients to test new general hypotheses about the role of CD1 and interleukin-22 in skin and thyroid autoimmunity.

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CD1 presentation of self glycolipids and lipopeptides to T cells. The particular molecules that function as antigens for autoreactive T cells that contribute to psoriasis, thyroiditis, diabetes, multiple sclerosis and other autoimmune diseases are poorly understood. Whereas current studies focus on peptide autoantigens for T cells, new research shows that human T frequently recognize lipids bound to CD1 proteins. New knowledge of the molecular structures of lipid auotantigens that contribute to autoimmunity could be used to develop diagnostic tests or intervene with immunological therapy in autoimmune diseases such as psoriasis.

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Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
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Cibotti, Ricardo
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Brigham and Women's Hospital
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Roy, Sobhan; Ly, Dalam; Li, Nan-Sheng et al. (2014) Molecular basis of mycobacterial lipid antigen presentation by CD1c and its recognition by ?? T cells. Proc Natl Acad Sci U S A 111:E4648-57
van Schaik, Barbera; Klarenbeek, Paul; Doorenspleet, Marieke et al. (2014) Discovery of invariant T cells by next-generation sequencing of the human TCR ?-chain repertoire. J Immunol 193:5338-44
Ly, Dalam; Moody, D Branch (2014) The CD1 size problem: lipid antigens, ligands, and scaffolds. Cell Mol Life Sci 71:3069-79
Van Rhijn, Ildiko; Gherardin, Nicholas A; Kasmar, Anne et al. (2014) TCR bias and affinity define two compartments of the CD1b-glycolipid-specific T Cell repertoire. J Immunol 192:4054-60
de Jong, Annemieke; Cheng, Tan-Yun; Huang, Shouxiong et al. (2014) CD1a-autoreactive T cells recognize natural skin oils that function as headless antigens. Nat Immunol 15:177-85
Ly, Dalam; Kasmar, Anne G; Cheng, Tan-Yun et al. (2013) CD1c tetramers detect ex vivo T cell responses to processed phosphomycoketide antigens. J Exp Med 210:729-41
Kasmar, Anne G; Van Rhijn, Ildiko; Magalhaes, Kelly G et al. (2013) Cutting Edge: CD1a tetramers and dextramers identify human lipopeptide-specific T cells ex vivo. J Immunol 191:4499-503
Leon, Luis; Tatituri, Raju V V; Grenha, Rosa et al. (2012) Saposins utilize two strategies for lipid transfer and CD1 antigen presentation. Proc Natl Acad Sci U S A 109:4357-64
Madigan, Cressida A; Cheng, Tan-Yun; Layre, Emilie et al. (2012) Lipidomic discovery of deoxysiderophores reveals a revised mycobactin biosynthesis pathway in Mycobacterium tuberculosis. Proc Natl Acad Sci U S A 109:1257-62
Zeissig, Sebastian; Blumberg, Richard S (2012) Primary immunodeficiency associated with defects in CD1 and CD1-restricted T cells. Ann N Y Acad Sci 1250:14-24

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