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Inhibition of protein geranylgeranylation specifically interferes with CD40-dependent B cell activation, resulting in a reduced capacity to induce T cell immunity

Item Type:Article
Title:Inhibition of protein geranylgeranylation specifically interferes with CD40-dependent B cell activation, resulting in a reduced capacity to induce T cell immunity
Creators Name:Shimabukuro-Vornhagen, A. and Zoghi, S. and Liebig, T.M. and Wennhold, K. and Chemitz, J. and Draube, A. and Kochanek, M. and Blaschke, F. and Pallasch, C. and Holtick, U. and Scheid, C. and Theurich, S. and Hallek, M. and von Bergwelt-Baildon, M.S.
Abstract:Ab-independent effector functions of B cells, such as Ag presentation and cytokine production, have been shown to play an important role in a variety of immune-mediated conditions such as autoimmune diseases, transplant rejection, and graft-versus-host disease. Most current immunosuppressive treatments target T cells, are relatively unspecific, and result in profound immunosuppression that places patients at an increased risk of developing severe infections and cancer. Therapeutic strategies, which interfere with B cell activation, could therefore be a useful addition to the current immunosuppressive armamentarium. Using a transcriptomic approach, we identified upregulation of genes that belong to the mevalonate pathway as a key molecular event following CD40-mediated activation of B cells. Inhibition of 3-hydroxy-3-methylglutaryl CoA reductase, the rate-limiting enzyme of the mevalonate pathway, by lipophilic statins such as simvastatin and atorvastatin resulted in a specific inhibition of B cell activation via CD40 and impaired their ability to act as stimulatory APCs for allospecific T cells. Mechanistically, the inhibitory effect resulted from the inhibition of protein geranylgeranylation subsequent to the depletion of mevalonate, the metabolic precursor for geranylgeranyl. Thus, inhibition of geranylgeranylation either directly through geranylgeranyl transferase inhibitors or indirectly through statins represents a promising therapeutic approach for the treatment of diseases in which Ag presentation by B cells plays a role.
Keywords:Antigen Presentation, B-Lymphocytes, CD40 Antigens, Cellular Immunity, Dendritic Cells, Gene Expression Regulation, Heptanoic Acids, Hydroxymethylglutaryl CoA Reductases, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Lymphocyte Activation, Mevalonic Acid, Primary Cell Culture, Protein Prenylation, Pyrroles, Signal Transduction, Simvastatin, T-Lymphocytes, Transcriptome
Source:Journal of Immunology
ISSN:0022-1767
Publisher:American Association of Immunologists (U.S.A.)
Volume:193
Number:10
Page Range:5294-5305
Date:15 November 2014
Official Publication:https://doi.org/10.4049/jimmunol.1203436
PubMed:View item in PubMed

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