Abstract
Expression of molecules involved in lipid homeostasis such as the low density lipoprotein receptor (LDLr) on antigen presenting cells (APCs) has been shown to enhance invariant natural killer T (iNKT) cell function. However, the contribution to iNKT cell activation by other lipoprotein receptors with shared structural and ligand binding properties to the LDLr has not been described. In this study, we investigated whether a structurally related receptor to the LDLr, known as LDL receptor-related protein (LRP), plays a role in iNKT cell activation. We found that, unlike the LDLr which is highly expressed on all immune cells, the LRP was preferentially expressed at high levels on F4/80+ macrophages (MΦ). We also show that CD169+ MΦs, known to present antigen to iNKT cells, exhibited increased expression of LRP compared to CD169- MΦs. To test the contribution of MΦ LRP to iNKT cell activation we used a mouse model of MΦ LRP conditional knockout (LRP-cKO). LRP-cKO MΦs pulsed with glycolipid alpha-galactosylceramide (αGC) elicited normal IL-2 secretion by iNKT hybridoma and in vivo challenge of LRP-cKO mice led to normal IFN-γ, but blunted IL-4 response in both serum and intracellular expression by iNKT cells. Flow cytometric analyses show similar levels of MHC class-I like molecule CD1d on LRP-cKO MΦs and normal glycolipid uptake. Survey of the iNKT cell compartment in LRP-cKO mice revealed intact numbers and percentages and no homeostatic disruption as evidenced by the absence of programmed death-1 and Ly-49 surface receptors. Mixed bone marrow chimeras showed that the inability iNKT cells to make IL-4 is cell extrinsic and can be rescued in the presence of wild type APCs. Collectively, these data demonstrate that, although MΦ LRP may not be necessary for IFN-γ responses, it can contribute to iNKT cell activation by enhancing early IL-4 secretion.
Highlights
The activation of invariant natural killer T cells has been shown to impact disease progression in mouse models of human disease such as multiple sclerosis [1,2], atherosclerosis [3,4] systemic lupus erythemathosus [5], cancer [6] and pathogenic infection [7]
LDL receptor-related protein (LRP) is differentially expressed on immune cells We measured LRP expression on immune cells isolated from tissues in which invariant natural killer T (iNKT) cells are known to reside and encounter antigen
CD169+ MWs express high levels of LRP Recent reports have shown that MWs expressing sialic acid binding immunoglobulin-like lectin 1 (Siglec-1, known as CD169) can mediate potent activation of iNKT cells in secondary lymphoid tissues [43]
Summary
The activation of invariant natural killer T (iNKT) cells has been shown to impact disease progression in mouse models of human disease such as multiple sclerosis [1,2], atherosclerosis [3,4] systemic lupus erythemathosus [5], cancer [6] and pathogenic infection [7]. INKT cells rearrange their T cell receptor (TCR) to express Va24-Ja18 and Va14-Ja18, respectively [8]. This allows iNKT cells from both species to recognize similar glycolipid antigens and elicit potent immune responses. INKT cell responses are known to enhance the initial phase of immunity by increasing NK, B and T cell activation This effect, known as immune transactivation, is thought to link innate immunity to adaptive immune responses [10] capable of fending off infection [11] and priming effector CD4+ and CD8+ T cells [12]. Modulation of iNKT cell responses is a potential therapeutic approach for cancer, autoimmunity and chronic inflammatory disorders
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