Self-glycerophospholipids activate murine phospholipid-reactive Tcells and inhibit iNKTcell activation by competing with ligands for CD1d loading
Self-glycerophospholipids activate murine phospholipid-reactive Tcells and inhibit iNKTcell activation by competing with ligands for CD1d loading
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DOI：
10.1002/eji.201847717
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发表时间：
2019-02-01
影响因子：
5.4
通讯作者：
Singh, Ram Raj
中科院分区：
文献类型：
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作者：
Halder, Ramesh Chandra;Tran, Cynthia;Singh, Ram Raj
Glycosphingolipids and glycerophospholipids bind CD1d. Glycosphingolipid-reactive invariant NKT-cells (iNKT) exhibit myriad immune effects, however, little is known about the functions of phospholipid-reactive Tcells (PLT). We report that the normal mouse immune repertoire contains Tcells, which recognize self-glycerophospholipids such as phosphatidic acid (PA) in a CD1d-restricted manner and don't cross-react with iNKT-cell ligands. PA bound to CD1d in the absence of lipid transfer proteins. Upon in vivo priming, PA induced an expansion and activation of Tcells in Ag-specific manner. Crystal structure of the CD1d:PA complex revealed that the ligand is centrally located in the CD1d-binding groove opening for TCR recognition. Moreover, the increased flexibility of the two acyl chains in diacylglycerol ligands and a less stringent-binding orientation for glycerophospholipids as compared with the bindings of glycosphingolipids may allow glycerophospholipids to readily occupy CD1d. Indeed, PA competed with -galactosylceramide to load onto CD1d, leading to reduced expression of CD1d:-galactosylceramide complexes on the surface of dendritic cells. Consistently, glycerophospholipids reduced iNKT-cell proliferation, expansion, and cytokine production in vitro and in vivo. Such superior ability of self-glycerophospholipids to compete with iNKT-cell ligands to occupy CD1d may help maintain homeostasis between the diverse subsets of lipid-reactive Tcells, with important pathogenetic and therapeutic implications.
