In addition to tumour models, mice lacking CD137 receptor or CD137 ligand expression have been studied in models of infection and

autoimmune disorders [2,7]. Given the key role of CD8+ T cells in controlling viral infection and the potent CD8+ T cell-inducing effect of agonistic CD137 mAb, CD137 triggering as a strategy to enhance the anti-viral response showed therapeutic potential. Conversely, even in the absence of CD137 expression, anti-viral immunity LDE225 seems to be functional, as CD137−/− mice showed reduced severity in a herpetic stromal keratitis (HSK) model [33]. With regard to bacterial infection, CD137−/− mice showed lower mortality in a model of polymicrobial sepsis induced by caecal ligation and puncture [34]. In comparison to WT controls, CD137−/− mice exhibited higher numbers of macrophages and neutrophils accomplished with better bacterial clearance and enhanced survival in this infection model. Similar results were observed after treatment with blocking anti-CD137L mAb, whereas the administration of CD137 agonistic mAb aggravated polymicrobial sepsis and decreased survival of WT mice [34]. Treatment with agonistic CD137 mAb has been demonstrated to efficiently prevent or even reverse autoimmune responses in murine studies,

including models PS-341 research buy for lupus, rheumatoid arthritis PRKD3 and experimental autoimmune encephalomyelitis [35–37]. Analysis of CD137−/− mice with regard to autoimmune disorders revealed a divergent outcome. Jeon et al. showed that CD137 gene deletion results in the improvement of atherosclerosis in hyperlipidaemic mice [38]. However, lprl CD137−/− mice show increased immune activation and develop a dramatic autoimmune phenotype leading to early mortality in a lupus model [39]. Recently, it has been demonstrated that CD137 deficiency protects against obesity-induced inflammation and metabolic disorders [40]. In general, CD137−/− mice show no defect in T cell development, as percentages of CD4+ and CD8+ T cells in spleen

and thymus were similar to WT mice under steady-state conditions [19]. In vitro stimulation of CD137−/− lymphocytes with anti-CD3 or mitogens revealed an increased proliferation relative to WT cells [19]. The observed hyperreactivity of cells from CD137−/− mice did not correlate with IL-2 secretion. Besides decreased IL-2 levels, the capacity for IL-4 and IFN-γ production was also diminished in CD137−/− cell cultures. In contrast to this unspecific stimulation, we did not detect significant differences in the proliferation of CD137−/− T cells when antigen-specific stimulation with OVA was used. Lee et al. reported enhanced CD4+ T cell responsiveness to protein antigen in CD137−/− mice [41].