Abstract 5065: Statins Modulate the Expression of Kruppel-Like Factor 2 in T Lymphocytes and Inhibit T Cell Responses
Kruppel-Like Factor 2 (KLF2) is a zinc -finger transcription factor, essential for maintenance of T cell quiescence and migration. Statins upregulate KLF2 expression in endothelial cells, but direct effects of statins on T cells are not characterized. We hypothesized that immunomodu-latory effects of statins are related partially to their influence on T cell KLF2 expression. Therefore, we characterized KLF2 expression pattern during different phases of T cell activation, examined the effects of Statins on KLF2 expression in T cells, and determined if Statins modulated pathologic T cell responses in a KLF2-dependent manner. Quantitative RT-PCR analyses indicated that KLF2 expression is relatively high in naïve mouse CD4+ and CD8+ T cells, but drops rapidly after TCR and CD28 co-stimulation and increases again as effector T cell are rested for several days. Interestingly, we also found that KLF2 is upregulated in CD8+ T cells that are functionally suppressed by FOXP3+ regulatory T cells. Effector T cells treated with four different lipophilic Statins (10 micromolar, 18h) enhanced expression of KLF2 and sphingosine 1 phosphate receptor (S1P1) and down-regulated interferon gamma expression. Statins also diminished T cell proliferation in response to TCR stimulation. Similar patterns of KLF2 expression and of Statin modulation of KLF2 were detected in human T cells, by qRT-PCR and Western blot analyses. Lovastatin (20mg/kg, i.p) treatment of C57B6 mice enhanced T cell KLF2 expression and induced resistance to T cell reactivation ex vivo. In a mouse model of myocarditis induced by adoptive transfer of heart-antigen-specific CTL, we found that simvastatin treatment of transferred T cells or retroviral-mediated over expression of KLF2 in the transferred T cells had similar effects; both reduced severity of myocarditis, down-regulated inflammatory gene expression in the hearts, and reduced cardiac draining lymph node responses. We conclude that both Statins and KLF2 modulate T cell activation and effector responses and that Statins upregulate KLF2 in T cells. Therefore, modulation of KLF2 by Statins may have therapeutic significance for cardiovascular diseases such as myocarditis and atherosclerosis.