Relationship Between Lipid Raft Modulation and Lymphocyte Function

Adaptive immune response relies on the activation of lymphocytes and the expansion of specific subsets in response to antigens. B lymphocytes represent an essential component of the humoral adaptive response through the synthesis of immunoglobulins, while T lymphocytes play a central role in cell-mediated immunity, and indeed the different T phenotypes orchestrate the immune response through different mechanisms. Two main aspects suggest a link between lipoproteins and adaptive immunity: first, the key receptors of B and T cells (BCR and TCR, respectively) are located in the lipid rafts, and their activity is modulated upon changes in the lipid raft composition and structure (Gupta and DeFranco 2007; Kabouridis and Jury 2008; Norata et al. 2012); second, Band T-cell trafficking and T-cell subset differentiation are controlled also by lysosphingolipids, mainly S1P (Mandala et al. 2002; Liu et al. 2010). Lipid rafts, which concentrate specific proteins, thus limiting their ability to freely diffuse over the plasma membrane, act as platforms, bringing together molecules essential for the activation of immune cells (immunological synapse), but also separating such molecules when the conditions for activation are not appropriate (Ehrenstein et al. 2005). Lipid rafts compartmentalize key signaling molecules during the different stages of B-cell activation including BCR-initiated signal transduction, endocytosis of BCR-antigen complexes, loading of antigenic peptides onto MHC class II molecules, MHC-II-associated antigen presentation to T cells, and receipt of helper signals via the CD40 receptor (Gupta and DeFranco 2007). Critical regulators of BCR signaling lose their association with membrane rafts in disease conditions; for instance, the LMP2A gene product of the EBV constitutively resides in membrane raft of EBV-transformed human B cells and blocks the entry of ligand-clustered BCRs and BCR translocation (Longnecker and Miller 1996). Furthermore, an alteration of Lyn, an accessory protein of BCR signaling, has been reported in patients with systemic lupus erythematosus (SLE) (Flores-Borja et al. 2005). It is therefore reasonable to speculate that HDL, by removing cholesterol from lipid rafts, could affect B-cell function. While a direct evidence for HDL effects on B-cell function is still lacking, several reports indicate that HDL and apoA-I stimulate cholesterol efflux from cells, leading to cholesterol depletion and disruption of lipid rafts, which induces profound functional changes (Smythies et al. 2010) in macrophages and also affects antigen presentation and TCR signaling (Gruaz et al. 2010; Norata and Catapano 2012).

The response of T lymphocytes to antigen is orchestrated by a number of molecules that cluster in lipid rafts. TCR complex integrity is vital for the induction of optimal and efficient immune responses (Baniyash 2004). In immune-mediated disorders, such as rheumatoid arthritis (RA) and SLE, and in chronic infectious diseases, T cells are dysfunctional with a characteristic loss of expression of the TCRζ chain (also called CD249), a key component of the TCR complex that couples surface antigen recognition with intracellular signal transduction (Baniyash 2004). Also other molecules associated with the TCR signaling are reduced or altered in autoimmune disorders, such as lymphocyte-specific protein tyrosine kinase (Lck) (Jury et al. 2006). T-cell immunological synapses are altered in circulating T cells from patients with coronary artery disease (CAD), and increased memory T-cell subsets were observed in particular in CAD patients with increased inflammatory markers (Ammirati et al. 2012a, b). Molecular mechanisms of how reduced levels of blood lipids can affect lipid rafts in immune-mediated disorders still remain to be addressed. However, atorvastatin reversed many of the signaling defects characteristic of T cells from patients with SLE (Jury et al. 2006). The possibility that atorvastatin targets lipid raft-associated signaling abnormalities in autoreactive T cells has been proposed as the rationale for its use in the therapy of autoimmune disease (Jury et al. 2006). This is further supported by a large observational study that demonstrated an association between persistence with statin therapy and reduced risk of developing RA (Chodick et al. 2010). More recently, Yvan-Charvet et al. reported that two key proteins involved in HDL cholesterol efflux such as ATP-binding cassette transporters ABCA1 and ABCG1 play a key role in hematopoietic stem and multipotential progenitor cell proliferation, thus further linking cholesterol efflux and lipid raft modulation to immune cell function (Yvan-Charvet et al. 2010a, b). Finally, a key role for apoA-I in controlling cholesterol-associated lymphocyte activation and proliferation in peripheral lymph nodes was observed in animal models (Wilhelm et al. 2009). The prevalence of classical CD14++/CD16but not of intermediate CD14++/CD16+ monocytes in hypoalphalipoproteinemia should also be taken into account as could impact on the different polarization on APC cells (Sala et al. 2013). More recently, Wang et al. (2012) demonstrated that HDL and apoA-I-induced cholesterol depletion and consequent disruption of plasma membrane lipid rafts in APCs inhibit their capacity to stimulate T-cell activation. This mechanism is highly dependent on the reduction of MHC class II molecules present on the cell surface following ABCA1 activation and on cholesterol efflux supporting a role for HDL in controlling also lymphocyte-mediated responses.

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