Soluble gp130 promotes intestinal epithelial hyperplasia during reovirus infection.

Soluble gp130 (sgp130) has been shown to suppress the inflammatory response of autoimmune pathologies; however, its effects on virus infection are not known. Here, we report that intraperitoneal treatment of mice with sgp130-Fc fusion protein at the time of oral reovirus serotype 3 infection resulted in altered morphopathological changes that were evident by less shortening of intestinal villi length and crypt depth after infection. That the effect mediated by sgp130 treatment was due to an increase in intestinal crypt cell proliferation was demonstrated by an increase in the number of crypt mitotic figures. This was further confirmed by increased immunoreactivity to the Cdc47 proliferation-associated antigen in crypts of sgp130-treated virus-infected mice compared to infected non-treated mice. These findings suggest that sgp130 may have a beneficial effect during intestinal virus infection by disrupting interleukin-6 trans-signalling, thereby reducing the local inflammatory response.

T-cell activation in the intestinal mucosa.

The vast majority of peripheral T cells exist as resting lymphocytes until a signal for activation has been received. In response to antigen, this activation involves ligation of the T-cell receptor (TCR) and signal transmission through the CD3 complex, which then initiates a cascade of intracellular events that lead to the expression of genes used in T-cell activation. T-cell activation also requires soluble mediators in the form of cytokines and chemokines that regulate the process in both positive and negative ways, and costimulatory signals received in conjunction with TCR/CD3 signaling are important in the activation of T cells. Unlike T cells in other peripheral immune compartments, small and large intestinal intraepithelial lymphocytes (IELs) bear some but not all properties of activated T cells, suggesting that they constitute a large population of 'partially activated' effector cells. Thus, regulation of the IEL activation process must be held in tight check, yet it must be ready to respond to foreign antigen rapidly and effectively. We discuss how costimulatory molecules may hold the key to controlling IEL activation through a multiphase process beginning with cells that have already entered into the early stage of activation.

Upregulation of ICOS on CD43+ CD4+ murine small intestinal intraepithelial lymphocytes during acute reovirus infection.

Murine intestinal intraepithelial lymphocytes (IELs) can be classified according to expression of a CD43 glycoform recognized by the S7 monoclonal antibody. In this study, we examined the response of S7+ and S7- IELs in mice during acute reovirus serotype 3 (Dearing strain) infection, which was confirmed by virus-specific real-time PCR. In vivo proliferation increased significantly for both S7- and S7+ IELs on day 4 post-infection as determined by BrdU incorporation; however, expression of the inducible costimulatory (ICOS) molecule, which peaked on day 7 post-infection, was upregulated on S7+ CD4+ T cells, most of which were CD4+8- IELs. In vitro ICOS stimulation by syngeneic peritoneal macrophages induced IFN-gamma secretion from IELs from day 7 infected mice, and was suppressed by treatment with anti-ICOS mAb. Additionally, IFN-gamma mRNA increased in CD4+ IELs on day 6 post-infection. These findings indicate that S7- and S7+ IELs are differentially mobilized during the immune response to reovirus infection; that the regulated expression of ICOS is associated with S7+ IELs; and that stimulation of IELs through ICOS enhances IFN-gamma synthesis during infection.

Selective upregulation of immune regulatory and effector cytokine synthesis by intestinal intraepithelial lymphocytes following CD43 costimulation.

The involvement of the CD43 molecule in the activation of mouse small intestinal intraepithelial lymphocytes (IELs) has been studied using a panel of twenty-two regulatory and effector immune response analytes. In the absence of stimulation in vitro, IELs produced low levels of CCL5 only. Upon CD3 stimulation, the activity of seven of twenty-two analytes was elevated relative to unstimulated cultures, including several proinflammatory cytokines and chemokines. Notably, CD3 stimulation in the presence of CD43 costimulation resulted in elevated levels of five analytes (interleukin-2, interferon-gamma, CCL5, granulocyte colony-stimulating factor, and granulocyte-monocyte colony-stimulating factor) above that produced by CD3 stimulation alone. That CD43 costimulation was responsible for elevated cytokine/chemokine activity was confirmed at the transcriptional level by real-time PCR for IFN-gamma and CCL5, and by ELISA for IFN-gamma. These findings open the way to a better understanding of the process by which T cells are activated in the intestinal epithelium.