The Moody laboratory seeks to answer questions regarding human T cell responses in autoimmunity and infectious disease. With an emphasis on tool building, our research uses whole cell screens to discover molecules and assign gene functions, thereby establishing previously unknown biological pathways that contribute to major diseases like tuberculosis and enteric fever.
From the immunology perspective, my group provided early findings relating to lipid antigens bound to human CD1 antigen presenting molecules. Expanding T cell recognition paradigms beyond recognition of peptides, we identified glycolipids presented by CD1b, phospholipids presented by CD1c and lipopeptides presented by CD1a. Studies of these model compounds supported two general models of antigen display. First, many antigens insert their lipid tails inside CD1, leaving phosphate, sugar or peptide head groups exposed for T cell receptor binding. Nearly opposite to this common situation, we later described small hydrophobic skin oils that activate T cells by inserting fully inside CD1. Their lack of protruding head groups exposes the surface of CD1 itself for direct recognition by T cell receptors.
Both models nucleated translational studies, whereby we worked with John Altman to develop CD1a, CD1b and CD1c tetramers. CD1 tetramers, with or without loaded antigens, identified previously unknown human T cell types, including abundant skin resident CD1a-autoreactive T cells, CD1b-reactive germline encoded mycolyl-reactive (GEM) T cells and CD1a-, CD1b- or CD1c-reactive gamma delta T cells. Given the non-polymorphic nature of the CD1 system, CD1a, CD1b and CD1c tetramers now represent a one-step reagent for staining T cells from any human in any disease. Our work supports new models of atopy whereby T cells directly recognize small molecular allergens rather than haptenated peptides, and human CD1 autoreactive T cells are now implicated in Crohn's disease, atopic dermatitis and psoriasis. Finally, we have eluted cellular self lipids from CD1 proteins to discover natural blockers of T cell response with therapeutic efficacy.
From the bacteriology perspective, we were surprised by the ready and repeated discovery of previously immunogenic molecules in Mycobacterium tuberculosis. After we realized that the M. tuberculosis lipidome was unsolved, we developed a discovery-oriented lipidomics profiling platform along with mass spectrometry annotation databases. We designed experiments to detect lipids and small molecules in pathogens versus their avirulent comparators, leading to the discovery the mannosylphosphomycoketide, deoxymycobactin, diphosphatidyltrehalose, tuberculosinylnucleoside and lysyl lipopeptide pathways in pathogenic bacteria. One of these pathways involving 1-tuberculosinyl adenosine appears to solve the decades old question regarding M. tuberculosis induced lysosomal failure and foam cell formation in tuberculosis.
This interdisciplinary program that merges genetics and chemical biology was recognized internationally by the Dutch National Team Science Award and the Wellcome Trust Collaborative award, as well as the Bill and Melinda Gates Foundation, Pew Foundation, Burroughs Wellcome Trust and the Mizutani Foundation. I have a strong interest in teaching scientific writing, which grew into a series of symposia offered worldwide at major universities and scientific meetings. My program has trained many young scientists for careers in research, including tenure track faculty at Columbia University, University of Washington, UCSF, UCSD, Harvard Medical School and other institutions.