Emerging Roles of CD1 and Lipids in Human Health and Disease

Acting alongside MHC proteins, which present peptide antigens, the CD1 system displays lipid antigens to T cells. Recent studies have defined two general mechanisms of T cell receptor (TCR) binding to human CD1a, CD1b, CD1c, and CD1d proteins. The classical mechanism involves TCR corecognition of lipid antigens and CD1 proteins. In the second mechanism, however, other αβ and γδ TCRs directly recognize the surface of CD1 in a lipid-independent manner, which partially bypasses the need to identify lipid autoantigens in disease states. In this article, we review the development of new experimental tools such as cell-wide lipidomic investigation of self-lipids, endogenously loaded CD1 tetramers, and human CD1 transgenic mice. These tools are revealing nonredundant roles for CD1 in immune response and are providing evidence that CD1-reactive T cells participate in disease lesions in human skin and gut. Further, the unexpected discovery of lipid blockers of CD1–TCR interaction supports new approaches to immunomodulation.