IFN-gamma represses IL-4 expression via IRF-1 and IRF-2.

Polarization of CD4(+) T helper cells toward either a Th1 or Th2 response can significantly influence host immunity to pathogens. IL-4 and IFN-gamma are the signature cytokines of Th2 and Th1 cells, respectively. IFN-gamma was shown to assist Th1 development by promoting IL-12 and IL-12 receptor expression. So far, direct influence of Th2 cytokine expression by IFN-gamma has not been described. We show here that IFN-gamma directly suppresses IL-4 gene expression. IRF-1 and IRF-2 induced by IFN-gamma bind to three distinct IL-4 promoter sites and function as transcriptional repressors. Our data demonstrate a direct negative feedback of IFN-gamma on expression of the Th2 cytokine gene IL-4 and, thus, provide evidence for another important mechanism by which IFNgamma assists Th1 and attenuates Th2 responses.

A phylogeny of planorbid snails, with implications for the evolution of Schistosoma parasites.

The Planorbidae represent one of the most important families of freshwater snails. They have a wide distribution and are significant both medically and economically as intermediate hosts for trematode worms. Digenetic trematodes of the genus Schistosoma cause schistosomiasis, a disease that infects 200 million people, and domestic animals throughout the tropics. Three of the four recognized species groups of Schistosoma rely on snails of the family Planorbidae to complete their life cycles. Each species group requires a specific planorbid genus-Bulinus, Biomphalaria, or Indoplanorbis. Our understanding of the relationships among the genera within the Planorbidae is rudimentary and based solely on internal anatomy and shell morphology. Two molecular markers, ribosomal 28S and actin exon 2, were sequenced and a phylogeny constructed for 38 taxa representing 16 planorbid genera. The phylogeny supports the division of the Planorbidae into two subfamilies, the Bulininae and Planorbinae. Interestingly, two representatives of the family Ancylidae fall within the Planorbidae highlighting the need for further analysis and possible reclassification of this group. A molecular based phylogeny of the genus Schistosoma was then mapped against the snail tree. The trees indicate that planorbid-transmitted Schistosoma appear not to be co-speciating with their current snail host lineages. Rather, host switching was prominent, including a switch involving two distantly related planorbid genera, Biomphalaria and Bulinus. Our study of the Planorbidae poses fundamental questions regarding how and when Schistosoma acquired new snail hosts, including how switches to relatively distant hosts are accomplished and why some available planorbids were not colonized.

Dysregulated T helper cell differentiation in the absence of interferon regulatory factor 4.

Certain IFN regulatory factor (IRF) transcription factors indirectly influence T helper (Th) cell differentiation by regulating the production of IL-12. Here, we show that IRF4 directly regulates Th cell differentiation in vitro and in vivo during murine leishmaniasis. In the absence of IRF4, IL-12-induced Th1 cell differentiation was compromised, while IL-4 failed to induce Th2 cell differentiation. Instead, IL-4 tended to induce Th1 cells, defined by production of IFN-gamma and TNF. Although early IL-4 signaling was normal in IRF4(-/-) Th cells, the protein GATA-3, a transcription factor critical for Th2 development, was not up-regulated following IL-4 treatment. Retroviral overexpression of GATA-3 rescued Th2 differentiation. Therefore, IRF4 deficiency manifests itself as severely dysregulated Th cell differentiation.