Background/Purpose: Lipids function as essential components of biological membranes, as signaling molecules, and as energy storage molecules. Glycerol-based phospholipids, called glycerophospholipids (GPL), are the most abundant membrane lipids. Their glycerol backbone is esterified to phosphoric acid, resulting in the formation of phosphatidic acid (PA), from which all other GPLs are formed by the addition of a polar headgroup like choline, ethanolamine, glycerol, inositol, and serine, producing the main phospholipids in the cell, namely phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylglycerol (PG), phosphatidylinositol (PI) and phosphatidylserine (PS), respectively. GPLs such as PA, PC, PE, PI, and PS, have been eluted and identified by mass spectrometry as natural human CD1d ligands, and PC and PE have been eluted from murine CD1d. However, the functions of T cells that recognize abundant self GPLs are not known. Here, we identified these T cells in various lymphoid organs in normal and autoimmune-prone mice, investigated cell-cell interactions, and determined their role in animal models of autoimmune disease. 

Methods:   CD1d tetramers were loaded with various GPL antigens, and cells analyzed by flow cytometry. Cell-cell interactions between GPL-reactive T cells and other immune cells were analyzed using in vivo and in vitro assays. In vivoeffects of GPLs were tested in autoimmune animal models.

Results:   CD1d tetramers loaded with GPLs, namely PA, PC, PE, PI, PS and BMP, identify 0.4–4% T cells in the lymphoid organs of normal and autoimmune-prone NZB/NZW and NZM.2328 mice. GPL-reactive T cells don’t recognize glycolipid-loaded tetramers and don’t respond to glycolipid αGalCer, suggesting that GPL-reactive T cells are distinct from other CD1d-restricted, invariant natural killer T cells. GPL-reactive T-cells expand, express CD69, and produce cytokines upon in vivo priming. However, all self-GPL antigens tested potently inhibited the proliferation and cytokine production by invariant natural killer T-cells via mobilization and migration of monocytic myeloid-derived suppressor cells into peripheral organs. These myeloid-derived suppressor cells inhibited invariant natural killer T-cells via interleukin-10. Treatment with a GPL antigen ameliorated autoimmune hepatitis, reduced pro-inflammatory cytokines and granulocyte accumulation, but recruited interleukin-10 producing myeloid derived suppressor cells that upon adoptive transfer protected against autoimmune disease in an animal model.

Conclusion: Normal immune repertoire contains T cells reactive to self GPLs, which ameliorate autoimmune disease via mobilization and migration of a subset of myeloid-derived suppressor cells. These novel observations have important implications for conditions with altered lipid metabolism and inflammation such as atherosclerosis and autoimmune disease. Acknowledgement: Supported in part by NICHD R03 to RCH, NICHD R21 and NIAID R01 to RRS.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-new-avenue-of-immune-regulation-conferred-by-self-glycerophospholipids-via-mobilization-and-migration-of-myeloid-derived-suppressor-cells/