The TNF-family cytokine TL1A drives IL-13-dependent small intestinal inflammation.

The tumor necrosis factor (TNF)-family cytokine TL1A (TNFSF15) costimulates T cells through its receptor DR3 (TNFRSF25) and is required for autoimmune pathology driven by diverse T-cell subsets. TL1A has been linked to human inflammatory bowel disease (IBD), but its pathogenic role is not known. We generated transgenic mice that constitutively express TL1A in T cells or dendritic cells. These mice spontaneously develop IL-13-dependent inflammatory small bowel pathology that strikingly resembles the intestinal response to nematode infections. These changes were dependent on the presence of a polyclonal T-cell receptor (TCR) repertoire, suggesting that they are driven by components in the intestinal flora. Forkhead box P3 (FoxP3)-positive regulatory T cells (Tregs) were present in increased numbers despite the fact that TL1A suppresses the generation of inducible Tregs. Finally, blocking TL1A-DR3 interactions abrogates 2,4,6 trinitrobenzenesulfonic acid (TNBS) colitis, indicating that these interactions influence other causes of intestinal inflammation as well. These results establish a novel link between TL1A and interleukin 13 (IL-13) responses that results in small intestinal inflammation, and also establish that TL1A-DR3 interactions are necessary and sufficient for T cell-dependent IBD.

Mercury enhances susceptibility to murine leishmaniasis.

The genetic background of mice infected with Leishmania major determines the response to infection, resulting in a resistant or susceptible phenotype. Susceptible mice develop a T-helper type 2 (Th2)-type immune response following infection distinguished by the development of interleukin (IL)-4 secreting T cells in the lymph node and spleen. In SJL mice, which normally heal L. major lesions, subtoxic doses of mercury induce an autoimmune syndrome characterized by an expansion of Th2 cells. In this study, we examined the effect of mercury administration on the outcome of L. major infection in SJL mice. We show that subtoxic doses of mercuric chloride (HgCl2) exacerbate disease outcome in SJL mice resulting in increased footpad swelling and increased parasite burdens. Furthermore, the effects of HgCl2 treatment on resistance to L. major are time-dependent. The nonhealing phenotype was observed only if mice had been treated with HgCl2 prior to L. major infection for at least 1 week, a timepoint at which mice treated with HgCl2 alone had increased splenocyte IL-4 production. HgCl2 treatment also increased production of serum immunoglobulin (Ig)E and IgG1, two IL-4 dependent isotypes. These results show that HgCl2 treatment enhances the susceptibility to L. major in SJL mice, consistent with the induction of host Th2 parameters. These findings have implications for the role of mercury contamination in areas of endemic leishmaniasis.

Leishmania amazonensis: the phagocytosis of amastigotes by macrophages.

In the present study, we examine the cell biology of Leishmania amastigote uptake by mammalian cells and compare this process to the phagocytosis of IgG-opsonized erythrocytes. We report that many aspects of amastigote uptake into macrophages resemble classical receptor-mediated phagocytosis. Parasite uptake requires energy expenditure by macrophages but not by parasites. Treating macrophages to prevent either energy metabolism or actin polymerization prevents amastigote uptake. The uptake of amastigotes by macrophages involves the colocalization of f-actin, paxillin, and talin to phagocytic cups that are formed around amastigotes during internalization. Treatment of macrophages with genestein, to inhibit protein phosphorylation, prevents amastigote uptake, indicating that this process, like receptor-mediated phagocytosis, depends on protein tyrosine phosphorylation. However, the amount and the pattern of protein tyrosine phosphorylation observed during amastigote uptake by macrophages is reduced relative to that observed during IgG-erythrocyte phagocytosis. The uptake of viable, but not heat-killed amastigotes, is associated with a decrease in the intensity of several specific macrophage proteins that are phosphorylated on tyrosine residues. In summary, although many features of amastigote uptake by macrophages resemble classical receptor-mediated phagocytosis, differences in macrophage protein phosphorylation during amastigote phagocytosis may contribute to the unique aspects of amastigote uptake and intracellular survival in macrophages.