Cholesterol lowering drug may influence cellular immune response by altering MHC II function

Abstract

There is a report that lowering of membrane cholesterol decreases expansion of the immune repertoire of CD4 + T cells, but not CD8 + T cells, in the thymic organ culture ( 3 ). The association of MHC II with either lipid raft or tetraspanin membrane domain is essential for effective antigen presentation ( 4,5 ). The treatment of antigen-presenting cells (APCs) with methyl ␤ -cyclodextrin (m ␤ -CD), known to deplete cellular cholesterol ( 6 ), reduces the antigen-presenting ability of MHC II without altering cell surface expression of MHC II ( 4 ). MHC II-restricted cognate interaction between APCs and CD4 + T cells is necessary for the initiation and propagation of immune response ( 7 ). Collectively the above information inclined to indicate that membrane cholesterol may play a decisive role in the expansion and maintenance of the immune repertoire, but the mechanism is largely unknown. This work is designed to understand how membrane cholesterol infl uences immune response.Cholesterol is important for lipid raft assembly ( 8 ) and also important for the formation of a tetraspanin-enriched microdomain ( 9 ). At a low cholesterol concentration, the diffusion coeffi cient of GPI-linked MHC II is reduced by a factor of 190 ( 10 ). There is a report that cholesterol depletion from the cell decreases the binding of anti-CCR5 antibodies directed to different sites of the receptor in a varying degree ( 11 ) The cholesterol lowering drug, statin, is extensively used in medical practice. There are clinical reports suggesting a better outcome of cardiac transplant in patients on statin therapy ( 1 ). Statin inhibits IFN-␥ -induced major histocompatibility complex class II (MHC II) expression but does not affect constitutive expression of MHC I and MHC II ( 2 ). Research, New Delhi, India and Network Project (Project NWP 0005 / BSC 0120 ; APC, antigen-presenting cell; CCM, cholesterol consensus motif; CRAC, cholesterol recognition/interaction amino-acid consensus; 3D, three-dimensional; m ␤ -CD, methyl ␤ -cyclodextrin; m ␤ -M ⌽ , methyl ␤ -cyclodextrin-treated macrophage; m ␤ -M ⌽ -CL, methyl ␤ -cyclodextrintreated macrophages treated with liposomal cholesterol; m ␤ -M ⌽ -CL-AN, methyl ␤ -cyclodextrin-treated macrophages treated with liposomal cholesterol analog; M ⌽ , macrophage; MHC I/II, major histocompatibility complex class I/II; mAb, monoclonal antibody; MFI, mean fl uorescence intensity; N-M ⌽ , normal macrophage; N-M ⌽ -CL, normal macrophages treated with liposomal cholesterol; PC, phosphatidylcholine; PEC, peritoneal exudate cell; TFE, trifl uoroethanol; TM, transmembrane; TM-MHC-II, transmembrane domain of major histocompatibility complex class II. This work was supported by the Council of Scientifi c and Industrial

Class II MHC/Peptide Interaction in Leishmania donovani Infection: Implications in Vaccine Design

“…The Ada-mediated enhancement of T cell responses by I-MFs could be explained on the basis of a favorable peptide exchange at the MHC-II molecule. Previously, we showed that there is a significant decrease in membrane cholesterol in L. donovani-I-MFs (56), and the transmembrane domain of MHC-II interacts with cholesterol with high affinity (K D 47 nM) (34). Our study also showed that depletion of membrane cholesterol alters conformation of MHC-II that leads to reduced p-MHC-II complex formation (34).…”

“…Previously, we showed that there is a significant decrease in membrane cholesterol in L. donovani-I-MFs (56), and the transmembrane domain of MHC-II interacts with cholesterol with high affinity (K D 47 nM) (34). Our study also showed that depletion of membrane cholesterol alters conformation of MHC-II that leads to reduced p-MHC-II complex formation (34). It is possible that decreases in membrane cholesterol in L. donovani infection alters the conformation of MHC-II, which may contribute to the defective p-MHC-II complex formation when intracellular parasite numbers are high.…”

Enhancement of Lytic Activity by Leptin Is Independent From Lipid Rafts in Murine Primary Splenocytes

“…To further investigate the mechanism involved in lytic activity, we investigated the potent role of lipid rafts of the effector cells. Indeed numerous proteins essential to the lytic mechanism are integrated into lipid rafts (Razzaq et al, ; Roy et al, ) just as leptin receptor (Frühbeck et al, ; Tu et al, ). Our results showed for the first time on primary spleen cells that cholesterol depletion reduces lytic activity by 31%.…”

Atherosclerosis and autoimmunity: a growing relationship

“…Human leukocyte antigen (HLA)‐II molecules have a key role in T lymphocytes activation and immune response hemostasis. Statins directly inhibit IFN‐γ‐induced expression of HLA‐II, and therefore act as a direct inhibitor of HLA‐II‐mediated T cell activation . This effect of statins is mediated by suppression of the inducible promoter IV of the HLA‐II transactivator CIITA, which is found in different cells of the immune system, such as monocyte and endothelial cells .…”