Self‐glycerophospholipids activate murine phospholipid‐reactive T cells and inhibit iNKT cell activation by competing with ligands for CD1d loading. Issue 2 (18th December 2018)

• Record Type: Journal Article
• Authors: Halder, Ramesh Chandra; Tran, Cynthia; Prasad, Priti; Wang, Jing; Nallapothula, Dhiraj; Ishikawa, Tatsuya; Wang, Meiying; Zajonc, Dirk M.; Singh, Ram Raj
• Is Part Of: European journal of immunology. Volume 49:Issue 2(2019)
• Page Start: 242
• Page End: 254
• Publication Date: 2018-12-18
• Subjects: CD1d -- iNKT cells -- phosphatidic acid -- phospholipid -- phospholipid‐reactive T cells; Immunology -- Periodicals; 616.079
• DOI: 10.1002/eji.201847717
• Languages: English
• ISSNs: 0014-2980

Abstract

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. Abstract : Glycerophospholipids (GPL), such as phosphatidic acid, bind the lipid antigen presenting molecule CD1d and activate phospholipid‐reactive T cells (PLT). Due to their less stringent binding orientation in the CD1d groove, GPLs compete with self and exogenously administered glycerosphingolipids (GSLs) to load onto CD1d, thus inhibiting the activation of iNKT cells.