Molecular studies of lipid presentation and T cell recognition of CD1c

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DESCRIPTION (provided by applicant): CD1c is a member of the CD1 family of proteins that are similar in structure to Major Histocompatibility Complex class I molecules. CD1 molecules have evolved unique lipid binding pockets (called A' and F') ideally suited for binding diverse lipid antigens via their hydrophobic hydrocarbon tails. CD1c falls into the Group 1 family of CD1 molecules found in humans; homologues are lacking in the mouse. Because we lack a tractable model by which to probe the function of Group 1 CD1 molecules, little is known about the immunological function of CD1c and the ¿¿ T cells that recognize it. Our recent crystal structure of CD1c shed light on this topic, revealing several unique features of this molecule that endows it with the capacity to bind diverse antigens. This structure also showed how CD1c presents a cell-wall lipid of Mycobacterium tuberculosis (MPM), a key potential target for vaccine development, and provides clues as to how a dodecameric N- terminally acylated lipopeptide ("lipo12") can also be presented. However, it is still unknown how CD1c presents other lipids, how this complex is recognized by ¿¿ T cells, and what characteristics dictate the ¿¿ T cell repertoire specific for CD1c (and whether this changes with different lipid antigens). In order to address these questions and more fully understand CD1c and its role in presenting diverse lipids to ¿¿ T cells, we will use the following strategies: our first aim, "To characterize the biophysical and structural details of CD1c lipid presentation." is focused on understanding the structural features of CD1c presentation and how intrinsic (lipid structure) and extrinsic (pH and chaperones) factors modulate CD1c's lipid repertoire. Our second aim, "To define how ¿¿ TCRs recognize CD1c/lipid ligands at the molecular level." is focused on using structural, biophysical and functional approaches to reveal how ¿¿ TCRs recognize CD1c/lipid at the molecular level. This is a key question relevant to globally understanding T cell recognition: How do diverse ¿¿ T cells "see" CD1 molecules? Is this recognition like classical ¿¿ TCR/MHC-like? Or are there features reminiscent of invariant Natural Killer T cell recognition of CD1d? Currently we have no information on this process. Finally, our third aim, "To characterize the repertoire of ¿¿ T cells that recognize CD1c." will focus on identifying the ¿¿ T cell repertoire that is CD1c responsive and to characterize these T cells for cell-surface markers (co-receptors, memory markers), effector functions (cytokine secretion and/or cytotoxicity) and the sequence of their TCRs, specifically to determine whether there are motifs in the CDR loops that are used in this recognition process. We will explore the human repertoire from health and diseased individuals and will make use of a humanized CD1c murine model to explore the T cell repertoire there. Currently our understanding of CD1c's contribution to human immunity is in its infancy, yet hints at its importance in pathogen recognition (such as M. tuberculosis) are already evident. Our proposal will expand our understanding of CD1c lipid presentation and the T cells that are reactive to it.