Apoptotic cells induce immunosuppression through dendritic cells: critical roles of IFN-gamma and nitric oxide

Apoptotic cells induce immunosuppression through unknown mechanisms. To identify the underlying molecular mediators, we examined how apoptotic cells induce immunoregulation by dendritic cells (DC). We found that administration of DC exposed to apoptotic cells (DC(ap)) strongly inhibited the expansion of lymphocytes in draining lymph nodes in vivo and the subsequent Ag-specific activation of these lymphocytes ex vivo. Unexpectedly, DC(ap) supported T cell activation to a similar extent as normal DC in vitro, leading to proliferation and IL-2 production, except that DC(ap) did not support T cell production of IFN-gamma. Surprisingly, when DC(ap) were cocultured with normal DC, they completely lost their ability to support T cell activation, an effect reversed by anti-IFN-gamma or inhibitors of inducible NO synthase (iNOS). As expected, exposure to apoptotic cells rendered DC(ap) capable of producing much more NO in response to exogenous IFN-gamma than normal DC. Furthermore, DC(ap) from iNOS(-/-) or IFN-gammaR1(-/-) mice were not inhibitory in vitro or in vivo. Therefore, the IFN-gamma-induced production of NO by apoptotic cell-sensitized DC plays a key role in apoptotic cell-mediated immunosuppression.     

MHC class II derived recombinant T cell receptor ligands protect DBA/1LacJ mice from collagen-induced arthritis

We previously demonstrated the therapeutic effects of MHC class II derived recombinant T cell receptor ligands (RTL), single-chain two domain complexes of the alpha1 and beta1 domains of MHC class II molecules genetically linked with an immunodominant peptide, in experimental autoimmune encephalomyelitis. In the current study, we produced a monomeric murine I-Aq-derived RTL construct covalently linked with bovine collagen type II peptide (bCII257-270) suitable for use in DBA/1LacJ mice that develop collagen-induced arthritis (CIA), an animal model of human rheumatoid arthritis, after immunization with bCII protein in CFA. In this study, we demonstrate that the I-Aq-derived RTLs reduced the incidence of the disease, suppressed the clinical and histological signs of CIA and induced long-term modulation of T cells specific for arthritogenic Ags. Our results showed that the I-Aq/bCII257-270 molecule could systemically reduce proinflammatory IL-17 and IFN-gamma production and significantly increase anti-inflammatory IL-10, IL-13, and FoxP3 gene expression in splenocytes. Moreover, I-Aq/bCII257-270 molecule could also selectively inhibit IL-1beta, IL-6, and IL-23 expression in local joint tissue. This is the first report demonstrating effective prevention of joint inflammation and clinical signs of CIA with an I-Aq-derived RTL, thus supporting the possible clinical use of this approach for treating rheumatoid arthritis in humans.     

Colonization with Heligmosomoides polygyrus suppresses mucosal IL-17 production

Helminth exposure appears to protect hosts from inappropriate inflammatory responses, such as those causing inflammatory bowel disease. A recently identified, strongly proinflammatory limb of the immune response is characterized by T cell IL-17 production. Many autoimmune type inflammatory diseases are associated with IL-17 release. Because helminths protect from these diseases, we examined IL-17 production in helminth-colonized mice. We colonized mice with Heligmosomoides polygyrus, an intestinal helminth, and analyzed IL-17 production by lamina propria mononuclear cells (LPMC) and mesenteric lymph node (MLN) cells. Colonization with H. polygyrus reduces IL-17A mRNA by MLN cells and inhibits IL-17 production by cultured LPMC and MLN cells. Helminth exposure augments IL-4 and IL-10 production. Blocking both IL-4 and IL-10, but not IL-10 alone, restores IL-17 production in vitro. Colonization of colitic IL-10-deficient mice with H. polygyrus suppresses LPMC IL-17 production and improves colitis. Ab-mediated blockade of IL-17 improves colitis in IL-10-deficient mice. Thus, helminth-associated inhibition of IL-17 production is most likely an important mechanism mediating protection from inappropriate intestinal inflammation.     

Longevity and fecundity of Japanese beetle (Popillia japonica) on foliage grown under elevated carbon dioxide

Atmospheric levels of carbon dioxide (CO(2)) have been increasing steadily over the last century. Plants grown under elevated CO(2) experience physiological changes that influence their suitability as food. Previous studies have found increased insect herbivory on plants grown under elevated CO(2). To determine effects of consuming foliage of soybean (Glycine max) grown under elevated CO(2) on adult survivorship and fecundity, Japanese beetles (Popillia japonica Newman) were fed for the duration of their adult lives leaves grown under elevated CO(2) (550 mumol/mol), under ambient atmosphere (370 mumol/mol), or grown under ambient atmosphere but supplemented with a solution of sugars. To determine effects of a diet of foliage grown under elevated ozone (O(3)), another anthropogenic gaseous pollutant, beetles in the laboratory were fed soybean leaves grown under elevated CO(2), elevated O(3), or a combination of both elevated gases. Leaf tissue was also analyzed for longevity-enhancing antioxidants, because increases in dietary antioxidants can increase lifespan. Lifespan of Japanese beetles was prolonged by 8-25% when fed foliage developed under elevated CO(2), but consuming foliage that had taken up sugars to approximately the same level as foliage grown under elevated CO(2) had no effect on fecundity or longevity. Females consuming elevated CO(2) foliage laid approximately twice as many eggs as females fed foliage grown under ambient conditions. Consuming foliage grown under elevated O(3) had no effect on fecundity. No significant differences in total antioxidant content of foliage from ambient and elevated CO(2) conditions were detected. Although the precise mechanism is unclear, by altering components of leaf chemistry other than sugar content, elevated CO(2) may increase populations of Japanese beetles and their impact on crop productivity.     

Interactions of Metarhizium anisoplae and tree-based mulches in repellence and mycoses against Coptotermes formosanus (Isoptera: Rhinotermitidae)

The use of mulch in urban landscapes has increased in the United States for the past decade. Tree-based organic mulches can supply Coptotermes formosanus Shiraki with food, moisture, and shelter. The current research contributes to mulch management technology in termite control. A choice test arena was designed to determine the repellence and mortality caused by commercial mulches treated with different concentrations of the fungus Metarhizium anisopliae (Metschnikoff) against C. formosanus. Each of six tree-based mulches (pine bark, pine straw, bald cypress, eucalyptus, water oak, and melaleuca) was coated with six conidial concentrations ranging from 1 x 10(3) to 1 x 10(8) conidia/ml. The foragers of C. formosanus were repelled significantly by the fungal-treated mulch substrates; the proportion of termites on fungal-treated mulch was usually <20% during the 28-d test. By day 28, >99% of the termites were killed in test arenas containing a chamber with mulch treated with 10(7) or 10(8) conidia/ml. M. anisopliae significantly reduced mulch consumption by 34-71%. Mulch consumption by the termites was negatively correlated with fungal concentration, and the type of mulch also affected consumption. The differences in termite foraging activities, mortality, and food consumption among mulches were usually confounded by differences in fungal concentrations of M. anisopliae. The results indicate that repellence and virulence of M. anisopliae conidia should significantly reduce the suitability of these six mulches as a habitat for C. formosanus.     

DeTEKting ubiquitination of APC/C substrates

Regulated protein degradation by the ubiquitin-proteasome pathway ensures the unidirectionality of mitotic progression by removing cell-cycle regulators required at earlier stages. The APC/C ubiquitin-protein ligase targets proteins by appending polyubiquitin degradation signals that are subsequently recognized by the 26S proteasome. Reporting in this issue, Jin et al. (2008) identify a TEK motif in both ubiquitin and substrates of APC/C that mediates assembly of these degradation signals.     

Resetting Behavior in a Model of Bursting in Secretory Pituitary Cells: Distinguishing Plateaus from Pseudo-Plateaus

We study a recently discovered class of models for plateau bursting, inspired by models for endocrine pituitary cells. In contrast to classical models for fold-homoclinic (square-wave) bursting, the spikes of the active phase are not supported by limit cycles of the frozen fast subsystem, but are transient oscillations generated by unstable limit cycles emanating from a subcritical Hopf bifurcation around a stable steady state. Experimental time courses are suggestive of such fold-subHopf models because the spikes tend to be small and variable in amplitude; we call this pseudo-plateau bursting. We show here that distinct properties of the response to attempted resets from the silent phase to the active phase provide a clearer, qualitative criterion for choosing between the two classes of models. The fold-homoclinic class is characterized by induced active phases that increase towards the duration of the unperturbed active phase as resets are delivered later in the silent phase. For the fold-subHopf class of pseudo-plateau bursting, resetting is difficult and succeeds only in limited windows of the silent phase but, paradoxically, can dramatically exceed the native active phase duration. J.V. Stern and H.M. Osinga contributed equally.