184: DUSP11 is a critical regulator of innate immune responses mediated by dendritic cells

Dual specificity phosphatases (DUSPs) have been shown to play a critical role in regulation of various cellular processes and aberrations in their expression patterns are associated with pathogenesis of wide range of diseases. The atypical dual-specificity phosphatase DUSP11 was previously demonstrated to bind to ribonucleic acid–ribonucleoprotein (RNA–RNP) complexes and RNA-splicing factors and is a p53 target gene. Recent in vitro studies highlighted the importance of this molecule in cell proliferation, cancer suppression and chronic inflammation. Our in vitro studies showed that DUSP11 expression is induced in dendritic cells upon stimulation by TLR ligands and in T cells upon CD3/CD28 activation suggesting the prominence of DUSP11 in immune responses. To examine the function of DUSP11 in regulating immune responses, we generated and analyzed DUSP11 deficient mice. We found that DUSP11 KO antigen presenting cells produce decreased levels of proinflammatory cytokines during innate immune responses and CD4 T cells have enhanced IL-2 production and proliferation in response to TCR activation compared to the wild type cells but no apparent defect in in vitro T cell differentiation. However, our in vivo experiments demonstrated that DUSP11 deficient mice are defective in antigen-specific T cell responses and that they are more susceptible to Listeria monocytogenes infection. Using dendritic cell (DC) and T cell co-culture experiments we established that the DUSP11 signalling in DCs eventually regulates CD4 T cell activation. Together, these results demonstrate that DUSP11 is critical for innate immune responses and that the defects in innate responses ultimately affect the adaptive immune responses. This supports the growing body of evidence that intrinsic pathways in innate immune cells can modulate T cell lineage differentiation. Currently our efforts are dedicated to understanding the molecular mechanisms regulated by DUSP11.