Role for lysosomal phospholipase A2 in iNKT cell-mediated CD1d recognition

Abstract

Invariant natural killer T (iNKT) cells recognize self lipid antigens presented by CD1d molecules. The nature of the self-antigens involved in the development and maturation of iNKT cells is poorly defined. Lysophospholipids are self-antigens presented by CD1d that are generated through the action of phospholipases A1 and A2. Lysosomal phospholipase A2 (LPLA2, group XV phospholipase A2) resides in the endocytic system, the main site where CD1d antigen acquisition occurs, suggesting that it could be particularly important in CD1d function. We find that Lpla2 −/− mice show a decrease in iNKT cell numbers that is neither the result of a general effect on the development of lymphocyte populations nor of effects on CD1d expression. However, endogenous lipid antigen presentation by CD1d is reduced in the absence of LPLA2. Our data suggest that LPLA2 plays a role in the generation of CD1d complexes with thymic lipids required for the normal selection and maturation of iNKT cells.antigen processing | lipid storage disease C D1d molecules are β 2 -microglobulin (β 2 m)-associated MHC class I homologs that bind lipid antigens and recycle between the plasma membrane and endocytic compartments. Endogenous and exogenous lipid binding can occur during transit through the secretory pathway and in the endocytic system, which is the main site of antigen loading (1). CD1d-lipid complexes are recognized by natural killer T (NKT) cells, a subset of T cells that shares characteristics of both the innate and adaptive arms of the immune system. NKT cells rapidly respond to stimulation by antigenpresenting cells (APCs) and release cytokines that can alter the strength and character of immune responses. They do so by transactivating, for example, NK cells, CD4+ and CD8 + T cells, and B cells, and by shifting cytokine responses to or from T helper (Th)1, Th2, and Th17 profiles. NKT cells have been shown to participate in inflammation, autoimmunity, cancer, and infectious diseases (2-4), and are characterized by the expression of both T-cell receptor (TCR) and NK cell markers. There are two main types: type I or invariant (iNKT), which express a semi-invariant TCR (Vα14-Jα18 in mice and Vα24-Jα18 in humans, paired with a restricted set of TCR-β chains, Vβ8.2, -7, or -2 in mice and Vβ11 in humans), and type II or noninvariant NKT cells that express more diverse TCRs (5-13).iNKT cells arise from double-positive (DP; CD4

Recognition of Lysophosphatidylcholine by Type II NKT Cells and Protection from an Inflammatory Liver Disease

“…Furthermore LPE generated in hepatocytes following hepatitis B infection can also stimulate type II NKT cells in murine liver (16). Interestingly although mouse type I NKT cells do not recognize lysophospholipids (16, 34), type I NKT-mediated lipid presentation is compromised in mice deficient in the lysosomal phosphatase A2 (PLA 2 ) (35). These data suggest that lysophospholipids in addition to being directly recognized by type II NKT cells may also be involved in antigen loading or CD1d-mediated presentation.…”

Lysosomal phospholipase A2: A novel player in host immunity to Mycobacterium tuberculosis

“…Only recently, Paduraru and colleagues described a role for LPLA 2 in iNKT cell-mediated CD1d recognition [14]. In other murine lysosomal storage disease models, the numbers of CD1d-restricted iNKT cells are often diminished, irrespective of the glycolipid species accumulated or the glycolipid catalytic/synthetic pathway genes affected [15].…”

Innate and Adaptive Immune Response in Fabry Disease

“…Besides, other therapeutic keys could arise from specific research on innate immunity. For example, lysosomal phospholipase A2 was reported to play a role in the generation of CD1d complexes and could therefore become a possible target like in coronary diseases (Paduraru et al 2013;The STABILITY Investigators 2014).…”