Statins inhibit Th1 cells by reducing the intracellular isoprenoids required for Ras and RhoA function

Cholesterol-lowering statin drugs, such as Lipitor and Zocor, have a fortuitous side effect: they ease T cell–driven autoimmune diseases such as multiple sclerosis (MS) and rheumatoid arthritis (RA). On page 401, Dunn and colleagues show that statins curb T cell activation by robbing the cells of isoprenoids, lipid intermediates formed during cholesterol biosynthesis.

The ability of statins to inhibit T cell proliferation has been appreciated for over a decade, but the mechanism was never fully understood. More recently, these drugs were shown to inhibit inflammatory T helper (Th)-1 responses and instead promote Th2 responses—a shift that protects mice against Th1-driven diseases such as RA and experimental autoimmune encephalomyelitis (EAE), a mouse model of MS.

A study in 2002 was the first to attribute the protective effect of statins in autoimmunity to a decrease in isoprenoids—lipids that attach to small GTP-binding proteins, allowing these proteins to associate with the cell membrane and transmit activating signals. In mice, interfering with the attachment of isoprenyl groups to the GTPase Rho in endothelial cells prevented T cells from crossing the blood–brain barrier on the road to causing EAE.

Dunn and colleagues now show that a similar mechanism is at play in EAE-causing T cells. T cells treated with atorvastatin (Lipitor) proliferated less and produced lower levels of the Th1 cytokine interferon (IFN)-γ compared with untreated cells. This inhibition was traced to defects in two GTP-binding proteins—Ras and RhoA—which failed to associate with the cell membrane in T cells from Lipitor-treated mice, thus preventing the activation of downstream signaling pathways required for T cell proliferation and the production of IFN-γ. Adding the relevant isoprenoids back to Lipitor-treated T cells reversed this effect.

Statins have a similar antiproliferative effect on tumor cells, an observation that prompted their testing as anticancer therapeutics. In fact, statins appear to have few drawbacks. So far, the use of these drugs has not been associated with either an increased incidence of Th2-driven diseases, such as asthma or allergies, or an increased risk of viral or bacterial infections that normally induce a protective Th1 response.