Title: Self-glycerophospholipids activate murine phospholipid-reactive T cells and inhibit iNKT cell activation by competing with ligands for CD1d loading.

Authors: Halder, Ramesh Chandra; Tran, Cynthia; Prasad, Priti; Wang, Jing; Nallapothula, Dhiraj; Ishikawa, Tatsuya; Wang, Meiying; Zajonc, Dirk M; Singh, Ram Raj

Published In Eur J Immunol, (2019 02)

Abstract: 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 T cells (PLT). We report that the normal mouse immune repertoire contains αβ T cells, 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 T cells 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 α-galactosylceramide to load onto CD1d, leading to reduced expression of CD1d:α-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 T cells, with important pathogenetic and therapeutic implications.

PubMed ID: 30508304

MeSH Terms: Animals; Antigens, CD1d*/chemistry; Antigens, CD1d*/genetics; Antigens, CD1d*/immunology; Crystallography, X-Ray; Dendritic Cells*/chemistry; Dendritic Cells*/immunology; Galactosylceramides/chemistry; Galactosylceramides/immunology; Lymphocyte Activation*; Mice; Mice, Knockout; Natural Killer T-Cells*/chemistry; Natural Killer T-Cells*/immunology; Phosphatidic Acids*/chemistry; Phosphatidic Acids*/immunology