It is noteworthy that statins have immunosuppressive and anti-inflammatory properties that seem to be mediated through nonsterol mevalonate products1. Statins also seem to promote a T helper 2 (TH2)-type cytokine bias in vivo2. The therapeutic relevance of these immunological effects is becoming increasingly apparent. The mechanism(s) by which statins decrease inflammation and autoimmunity are still under debate. In the May issue of Nature Reviews Immunology, Greenwood and co-workers3. , reviewed excellently the several potential explanations for this immunomodulatory activity of statins. However, they do not discuss the inhibitory effect of statins on human γδ T cells, which might also contribute to their immunosuppressive activity.
γδ T cells are a minor T cell population with a unique pattern of antigen recognition. In humans, most circulating γδ T cells express a T cell receptor comprised of Vγ9 and Vδ2 (REF. 4) chains, which directly recognize non-peptide ligands without requiring them to be presented by MHC molecules5. The non-peptide ligands, referred to as phosphoantigens, comprise isoprenoid pathway metabolites, such as isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP), that are derived from microorganisms6 and tumour cells7. Accordingly, pharmacological agents that cause accumulation of such metabolites, for example, the aminobisphosphonates8 sensitize cells to Vγ9Vδ2 T cell recognition. Blockade of 3 hydroxy-3 methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme of the mevalonate pathway, prevents both accumulation of mevalonate metabolites and recognition by Vγ9Vδ2 T cells9.
Vγ9Vδ2 T cells are attractive candidates for mediators of autoimmune disease. Accordingly, Vγ9Vδ2 T cells have been found in brain lesions from patients with multiple sclerosis, but not other inflammatory brain diseases10,11. Increases in the number of Vγ9Vδ2 T cells are also associated with systemic lupus erythematosus, rheumatoid arthritis, autoimmune thyroid conditions, autoimmune liver disease and Behcet’s disease (reviewed in REFS 10,11). In patients with Behcet’s disease, Vγ9Vδ2 T cell activation and their production of pro-inflammatory cytokines and cytotoxic molecules (for example, granzyme A) is correlated with disease activity and progression and so are probably involved in disease pathogenesis12,13.
Recently, it has been shown that Vγ9Vδ2 T-cell proliferation, activation and cytokine (interferon-δ tumour-necrosis factor and interleukin 6) production is prevented by mevastatin or lovastatin, which inhibit HMG-CoA reductase upstream of farnesyl pyrophosphate synthase and prevent the synthesis of IPP and/or DMAPP14,15. By contrast, desoxolovastatin, an analogue of lovastatin that can not inhibit HMG-CoA reductase, had no effect15. This finding could explain the side-effects observed after administration of aminobisphosphonates in some patients, such as an increase in body temperature or flu-like symptoms that resemble a typical acute-phase response.
Therefore, the evidence discussed here provides a further mechanism by which statins could have anti-inflammatory effects, by showing that these drugs inhibit the activation of human peripheral blood Vγ9Vδ2 T cells in response to endogenous nonsterol mevalonate products.
Francesco Dieli and Nadia Caccamo
This correspondence relates to the article:
Statin therapy and autoimmune disease: from protein prenylation to immunomodulation
Nature Rev. Immunol. 6, 358–370 (2006)
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Dieli, F., Caccamo, N. Immunomodulatory role of statins in autoimmune disease: is there a role for human γδT cells?. Nat Rev Immunol 6, 564 (2006). https://doi.org/10.1038/nri1839-c1
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DOI: https://doi.org/10.1038/nri1839-c1
