Cluster of differentiation 1c (CD1c)-dependent self-reactive T cells are abundant in human blood, but self-antigens presented by CD1c to the T-cell receptors of these cells are poorly understood. Here we present a crystal structure of CD1c determined at 2.4 Å revealing an extended ligand binding potential of the antigen groove and a substantially different conformation compared with known CD1c structures. Computational simulations exploring different occupancy states of the groove reenacted these different CD1c conformations and suggested cholesteryl esters (CE) and acylated steryl glycosides (ASG) as new ligand classes for CD1c. Confirming this, we show that binding of CE and ASG to CD1c enables the binding of human CD1c self-reactive T-cell receptors. Hence, human CD1c adopts different conformations dependent on ligand occupancy of its groove, with CE and ASG stabilizing CD1c conformations that provide a footprint for binding of CD1c self-reactive T-cell receptors.CD1 | lipid antigen | antigen presentation | T cell | cholesteryl ester C luster of differentiation 1 (CD1) proteins are a family of MHC class I-like glycoproteins that present lipid antigens to T cells. CD1 restricted T cells are abundant in humans and play important roles in host defense and immune regulation. Human CD1 proteins comprise five CD1 isoforms, CD1a, CD1b, CD1c, CD1d, and CD1e, which exhibit different intracellular trafficking behaviors and ligand binding preferences (1). Structurally, the main differences between these CD1 isoforms lie in the architecture of their lipophilic ligand binding grooves. Whereas all CD1 isoforms share a highly conserved A′ channel (or pocket) for binding C18-C26 acyl chains, specialization is provided by further connecting channels (2-7). In CD1a, the A′ channel is "fused" to a wide and shallow F′ channel, enabling binding of lipopeptides such as mycobacterial didehydroxymycobactin (DDM) (8). CD1b features a unique T′ tunnel that connects A′ and F′, thereby forming a "superchannel" for accommodating very long acyl chains (e.g., mycobacterial mycolates) (2, 4). CD1d, the only isoform also conserved in rodents, exhibits a twobranched ligand binding groove with two linear channels A′ and F′ connected near the main portal into the groove, known as the F′ portal. A similar two-branched arrangement of A′ and F′ is seen in CD1e, the only CD1 isoform not expressed on the cell surface. Compared with CD1d, CD1a, and CD1b, the portal into the groove in CD1e is widely exposed, consistent with its known role in lipid transfer processes inside lysosomes (6).CD1c presents foreign-(9, 10) as well as self-lipid antigens to T cells (11). Two recent crystal structures of human CD1c revealed a two-branched design similar to that of CD1d and CD1e, with two channels A′ and F′ connecting near the groove portal. In these structures, a mycobacterial phosphomycoketide (PM) or mannosyl-β1-phosphomycoketide (MPM) occupied the A′ channel, whereas an undefined short ligand was present in the F′ channel (7, 12). The spatial arrangement of...

hermsii. These data show that ACGal is present in all clinically important B. burgdorferi species, and that specific antibodies against this compound are frequently found during LD. ACGal may thus be an interesting tool for improving diagnostics as well as for novel vaccination strategies.

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The German National Cohort (NAKO) is a multidisciplinary, population-based prospective cohort study that aims to investigate the causes of widespread diseases, identify risk factors and improve early detection and prevention of disease. Specifically, NAKO is designed to identify novel and better characterize established risk and protection factors for the development of cardiovascular diseases, cancer, diabetes, neurodegenerative and psychiatric diseases, musculoskeletal diseases, respiratory and infectious diseases in a random sample of the general population. Between 2014 and 2019, a total of 205,415 men and women aged 19–74 years were recruited and examined in 18 study centres in Germany. The baseline assessment included a face-to-face interview, self-administered questionnaires and a wide range of biomedical examinations. Biomaterials were collected from all participants including serum, EDTA plasma, buffy coats, RNA and erythrocytes, urine, saliva, nasal swabs and stool. In 56,971 participants, an intensified examination programme was implemented. Whole-body 3T magnetic resonance imaging was performed in 30,861 participants on dedicated scanners. NAKO collects follow-up information on incident diseases through a combination of active follow-up using self-report via written questionnaires at 2–3 year intervals and passive follow-up via record linkages. All study participants are invited for re-examinations at the study centres in 4–5 year intervals. Thereby, longitudinal information on changes in risk factor profiles and in vascular, cardiac, metabolic, neurocognitive, pulmonary and sensory function is collected. NAKO is a major resource for population-based epidemiology to identify new and tailored strategies for early detection, prediction, prevention and treatment of major diseases for the next 30 years.