- CD1 Presentation of Self Lipids to Human T cells ? D. Branch Moody T cells play a central role in the pathogenesis of human autoimmune diseases, including allergy and drug hypersensitivity syndromes. For decades studies of T cell autoantigens have emphasized peptide antigens bound to MHC proteins. This proposal investigates the basis by which self lipid antigens bind to human CD1 antigen presenting molecules, leading to autoreactive T cell responses. This competing renewal builds on an existing program of development that has invented human CD1a and CD1b tetramers and used them to discover previously unknown lipid autoantigens for T cells, including squalene and phosphatidylglycerol. To provide a general basis for lipid epitope mapping, we will use mass spectrometry to broadly identify many hundreds of self lipids that bind to CD1 proteins in human cells. Using tetramers, we will identify and clone autoreactive T cell receptors and measure their binding to CD1-self lipid complexes. Building on recently published studies showing that CD1a autoreactive T cells are increased in patients with allergy syndromes, we will measure CD1a-reactive T cell responses in human cohorts. Finally, we will investigate a new mechanism by which CD1a proteins present common skin irritants from clinical patch tests to T cells, bypassing mechanisms that relate to peptide haptenization. Overall, these studies will extend the spectrum of natural T cell autoantigens to include self lipids and investigate their roles in common allergic diseases.
- CD1 Presentation of Self Lipids to human T cells ? D. Branch Moody T cells play a central role in human allergy and hypersensitivity syndromes. Bypassing conventional approaches that emphasize peptide autoantigens, this proposal seeks to identify lipid antigens that stimulate autoreactive T cell responses and allergies in humans. Chemical optimization of lipid antigens offers the possibility to diagnose hypersensitivity syndromes and modulate T cell mediated allergy.
| Cotton, Rachel N; Shahine, Adam; Rossjohn, Jamie et al. (2018) Lipids hide or step aside for CD1-autoreactive T cell receptors. Curr Opin Immunol 52:93-99 |
| Wun, Kwok S; Reijneveld, Josephine F; Cheng, Tan-Yun et al. (2018) T cell autoreactivity directed toward CD1c itself rather than toward carried self lipids. Nat Immunol 19:397-406 |
| Shahine, Adam; Van Rhijn, Ildiko; Cheng, Tan-Yun et al. (2017) A molecular basis of human T cell receptor autoreactivity toward self-phospholipids. Sci Immunol 2: |
| 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 |
| Moody, D Branch; Cotton, Rachel N (2017) Four pathways of CD1 antigen presentation to T cells. Curr Opin Immunol 46:127-133 |
| Huang, Shouxiong; Moody, D Branch (2016) Donor-unrestricted T cells in the human CD1 system. Immunogenetics 68:577-96 |
| Roy, Sobhan; Ly, Dalam; Castro, Caitlin D et al. (2016) Molecular Analysis of Lipid-Reactive V?1 ?? T Cells Identified by CD1c Tetramers. J Immunol 196:1933-42 |
| Kasprowicz, Victoria O; Cheng, Tan-Yun; Ndung'u, Thumbi et al. (2016) HIV Disrupts Human T Cells That Target Mycobacterial Glycolipids. J Infect Dis 213:628-33 |
| Van Rhijn, Ildiko; Moody, D Branch (2015) CD1 and mycobacterial lipids activate human T cells. Immunol Rev 264:138-53 |
| Godfrey, Dale I; Uldrich, Adam P; McCluskey, James et al. (2015) The burgeoning family of unconventional T cells. Nat Immunol 16:1114-23 |
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