Ups and Downs of Mucosal Cellular Immunity against Protozoan Parasites

The intestinal mucosa provides both a physiologic and immunologic barrier to a wide range of microorganisms and foreign substances. In general, the mucosal immune system is homeostatic despite the considerable antigenic load in the intestine. When an imbalance does occur in the regulation of this response, gut barrier dysfunction and inflammatory bowel disease are observed. Protozoan parasites that gain access to the host through the mucosal tissue of the alimentary tract may influence the development of such intestinal inflammatory disorders. Gut inflammatory diseases are associated with the production of various inflammatory cytokines including interleukin-1 (IL-1), IL-8, or tumor necrosis factor alpha (TNF-α) and gamma interferon (IFN-γ) that may be produced by mucosal epithelial cells or by neighboring cells from the immune system. These immune products may act as chemoattractants (chemokines) for specific inflammatory cells, including macrophages, monocytes, neutrophils, and lymphocytes, that contribute to the mucosal inflammation. Elevated levels of nitric oxide (NO)-derived metabolites have been associated with these Th1-mediated inflammatory disorders. Although this proinflammatory response may be necessary to clear the infection it may invoke pathologic and potentially destructive changes in the tissue. In normal physiologic conditions, a homeostatic balance is maintained and the inflammatory disorders are prevented by downregulation of the immune response in the intestine. A number of immune mediators are potentially involved in downregulation of the inflammatory response. Two cytokines, in particular, transforming growth factor β (TGF-β) and IL-10, appear to be candidates responsible for the downregulation of NO production. TGF-β is a potent immunoregulatory agent that affects proliferation (1, 82), the state of activation (69, 73) and differentiation (76) of the T-cell response. TGF-β may impair IL-12 production (74) that stimulates IFN-γ synthesis and the proliferation of both T and NK cells. TGF-β alters expression of T-cell costimulatory molecules, in particular, CD40/CD154 interactions that are responsible for the production of IL-12 (91). Recent studies involving genetically impaired mice for some members of the TGF-β family emphasize the role of TGF-β as a master regulator of immune cell function (53). Another cytokine associated with downregulation is IL-10 that can be produced by a large variety of immune cells, including T lymphocytes, that express the Th2 phenotype, B cells, and macrophages. IL-10 can downregulate IFN-γ synthesis by Toxoplasma gondii-stimulated NK cells (88) and T cells (41) as well as a wide variety of macrophage-derived proinflammatory monokines (66), suggesting a critical role in macrophage effector functions against different pathogens (26). IL-10 inhibits IFN-γ synthesis by NK and Th1 lymphocytes via inhibition of macrophage IL-12 synthesis (34). IL-10 is associated with the downregulation of the expression of costimulatory molecules, which are implicated in the immunopathology observed after T. gondii infection (94). Intestinal immune homeostasis is dependent upon the successful interaction of several compartments within the intestinal tract. These include organized secondary lymphoid organs, such as mesenteric lymph nodes, Peyer's patches, and leukocytes that are dispersed throughout the intestinal wall and within the mucosa, the intraepithelial lymphocytes (IEL). Epithelial cells or enterocytes lining the alimentary tract serve both as a physiologic barrier separating the lumen from underlying tissues and as a source of immune inflammatory products. These enterocytes or immunocytes play a critical role in mucosal immunophysiology that in part consists of a paracrine network between enterocytes and the underlying immune and inflammatory cells.