Cholesteryl esters stabilize human CD1c conformations for recognition by self-reactive T cells.

Progress of Theoretical Physics Supplement Pub Date : 2016-03-01 Epub Date: 2016-02-16 DOI:10.1073/pnas.1519246113
Salah Mansour, Anna S Tocheva, Chris Cave-Ayland, Moritz M Machelett, Barbara Sander, Nikolai M Lissin, Peter E Molloy, Mark S Baird, Gunthard Stübs, Nicolas W J Schröder, Ralf R Schumann, Jörg Rademann, Anthony D Postle, Bent K Jakobsen, Ben G Marshall, Rajendra Gosain, Paul T Elkington, Tim Elliott, Chris-Kriton Skylaris, Jonathan W Essex, Ivo Tews, Stephan D Gadola
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Abstract

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.

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胆固醇酯能稳定人类 CD1c 的构象,使其能被自我反应 T 细胞识别。
人体血液中存在大量依赖分化簇 1c(CD1c)的自我反应 T 细胞,但人们对 CD1c 向这些细胞的 T 细胞受体传递的自我抗原却知之甚少。在这里,我们展示了在 2.4 Å 处测定的 CD1c 晶体结构,它揭示了抗原沟的配体结合潜能的扩展,以及与已知 CD1c 结构相比大不相同的构象。探索凹槽不同占据状态的计算模拟重现了这些不同的 CD1c 构象,并提出胆固醇酯 (CE) 和酰化甾基糖苷 (ASG) 是 CD1c 的新配体类别。为了证实这一点,我们证明了 CE 和 ASG 与 CD1c 的结合能使人类 CD1c 自我反应 T 细胞受体结合。因此,人类 CD1c 可根据配体对其沟槽的占据情况采用不同的构象,CE 和 ASG 可稳定 CD1c 的构象,为 CD1c 自我反应 T 细胞受体的结合提供足迹。
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