For many years, human ?? T cells were thought solely to recognize peptides bound to MHC proteins. Early stages of work on this parent grant provided broad evidence that non-polymorphic CD1 proteins (CD1a, CD1b, CD1c) display mycobacterial lipids to human ?? T cells. After generating working tetramers comprised of human CD1a, CD1b and CD1c proteins, our published data show that polyclonal, lipid-specific T cells exist as cell populations in tuberculosis (TB) patients and possess effector functions (TNF and IFN-?) that are known to protect the human host. Further, CD1c tetramers detected polyclonal ?? T cells recognizing mycobacterial mycoketides. CD1b tetramers detected a previously unknown human T cell type: germline-encoded mycolylreactive (GEM) T cells. GEM T cells have a degree of T cell receptor (TCR) conservation, which is equivalent to NKT cells or MAIT cells, but GEM T cells function to recognize CD1b. Building on these new reagents and recent success in solving the crystal structure of CD1a-lipid-TCR, the renewal will carry out detailed biophysical analyses of ternary TCR-CD1-mycobacterial lipid interactions involving both ?? and ?? TCRs. Turning to translational questions in TB disease, we will collaborate with Socios En Salud to determine the immunodominant mycobacterial lipids stimulating human response in latent and active TB. Over the past 3 years, we validated guinea pig CD1b and CD1c tetramers and anti-CD1 antibodies to create a tractable small animal model of in vivo T cell response to CD1. Now we propose to measure the duration and magnitude of response to lipid antigens and determine whether CD1 presented lipids can protect against M. tuberculosis infection. Finally, based on the discovery of GEM T cells, we propose to detect networks of interdonor conserved TCRs in the humans. These studies move beyond NKT cells and MAIT cells to detect stereotyped human T cell response to CD1a, CD1b and CD1c bound to mycobacterial lipids. Such studies seek to reveal a currently unappreciated structure of a public human T cell response. Such a system would change general views of the structure of the human T cell repertoire and the particular TCRs identified might be used for immunodiagnosis of TB infection.
Better diagnosis and treatment of TB is needed to contain the worldwide epidemic, which killed more than one million people last year. Whereas most technology development related to T cells derives from study of peptide antigens, human T cells broadly respond to mycobacterial lipids that are displayed on the surface of CD1 proteins. Further, recent studies show that CD1- reactive T cell responses to lipids are similar among individual patients. Here we propose to measure human T cell response to CD1 and mycobacteria during tuberculosis infection to identify lipids that stimulate immune response and T cell receptor patterns that can be use for diagnosis.
|Van Rhijn, Ildiko; Iwany, Sarah K; Fodran, Peter et al. (2017) CD1b-mycolic acid tetramers demonstrate T-cell fine specificity for mycobacterial lipid tails. Eur J Immunol 47:1525-1534|
|Moody, D Branch; Suliman, Sara (2017) CD1: From Molecules to Diseases. F1000Res 6:1909|
|Moody, D Branch (2017) How T cells grasp mycobacterial lipid antigens. Proc Natl Acad Sci U S A 114:13312-13314|
|Moody, D Branch; Cotton, Rachel N (2017) Four pathways of CD1 antigen presentation to T cells. Curr Opin Immunol 46:127-133|
|Gras, Stephanie; Van Rhijn, Ildiko; Shahine, Adam et al. (2016) T cell receptor recognition of CD1b presenting a mycobacterial glycolipid. Nat Commun 7:13257|
|Larrouy-Maumus, Gérald; Marino, Leonardo B; Madduri, Ashoka V R et al. (2016) Cell-Envelope Remodeling as a Determinant of Phenotypic Antibacterial Tolerance in Mycobacterium tuberculosis. ACS Infect Dis 2:352-360|
|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|
|Martinot, Amanda J; Farrow, Mary; Bai, Lu et al. (2016) Mycobacterial Metabolic Syndrome: LprG and Rv1410 Regulate Triacylglyceride Levels, Growth Rate and Virulence in Mycobacterium tuberculosis. PLoS Pathog 12:e1005351|
|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|
|Jarrett, Rachael; Salio, Mariolina; Lloyd-Lavery, Antonia et al. (2016) Filaggrin inhibits generation of CD1a neolipid antigens by house dust mite-derived phospholipase. Sci Transl Med 8:325ra18|
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