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

J Immunol. 2014 Nov 15;193(10):5294-305. doi: 10.4049/jimmunol.1203436. Epub 2014 Oct 13.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigen Presentation / drug effects
  • Atorvastatin
  • B-Lymphocytes / drug effects*
  • B-Lymphocytes / enzymology
  • B-Lymphocytes / immunology
  • CD40 Antigens / antagonists & inhibitors*
  • CD40 Antigens / genetics
  • CD40 Antigens / immunology
  • Dendritic Cells / drug effects
  • Dendritic Cells / immunology
  • Gene Expression Regulation
  • Heptanoic Acids / pharmacology
  • Humans
  • Hydroxymethylglutaryl CoA Reductases / genetics
  • Hydroxymethylglutaryl CoA Reductases / immunology
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
  • Immunity, Cellular / drug effects*
  • Lymphocyte Activation / drug effects
  • Mevalonic Acid / metabolism
  • Primary Cell Culture
  • Protein Prenylation / drug effects*
  • Pyrroles / pharmacology
  • Signal Transduction
  • Simvastatin / pharmacology
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology
  • Transcriptome / immunology*


  • CD40 Antigens
  • Heptanoic Acids
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Pyrroles
  • Atorvastatin
  • Simvastatin
  • Hydroxymethylglutaryl CoA Reductases
  • Mevalonic Acid

Associated data

  • GEO/GSE54017