198 38]. As demonstrated in gnotobiotic (lacking microbiota) mouse studies, development of gut immunity is strongly influenced by the intestinal microbiota. It was recently shown that some bacteria of the genus Clostridia (phylum Firmicutes), termed segmented filamentous bacteria (SFB), are essential to the development of Th17 cells in the mouse gut [39–42]. One host factor that influences the composi- tion of the gut microbiota, including colonization by SFB, is the expression of antimicrobial peptides such as defensins [42]. Expression of a human specific alpha defensin (DEFA5) in the mouse dramatically changes the microbiota composition, including the loss of SFB [42]. Concomitant with these changes in the microbiota, fewer IL-17 producing T cells were isolated from the lamina propria. In contrast, mice colonized with SFB had an increased expression of genes associated with inflammation and antimicrobial defense and were subsequently more resistant to infection with C. rodentium [41]. These recent studies demonstrate that specific members of the gut microbiota can shape aspects of the mucosal barrier. Th17 Cytokines Control Pathogen Dissemination from the Mucosa The role IL-17 and IL-22 play during mucosal infections has become apparent following several studies that employed mice lacking these cytokines (IL-17A, IL-17F, IL-22), their receptors (IL-17Ra, IL-17Rc), or upstream cytokines responsible for their induction (IL-23 p19 deficient mice). During colonic infection with C. roden- tium, IL-17A, IL-17F, and IL-22 appear to play a role in controlling the severity of gut pathology [34, 43]. In rhesus macaques, depletion of Th17 cells by SIV results in alteration of the mucosal barrier and increased dissemina- tion of S. typhimurium to the mesenteric lymph nodes. Moreover, IL-17Ra−/− mice have increased translocation of S. typhimurium to the mesenteric lymph nodes and spleen [36]. Ileitis caused by Toxoplasma gondii infection is dependent on IL-23 stimulated IL-22 production by CD4+ T cells in the small intestinal lamina propria [44]. As illustrated in these and other studies, IL-17 and IL-22 upregulation appear to comprise a stereotypic response to infection with mucosal pathogens. Receptors of IL-17A and IL-17F (IL-17Ra and IL-17Rc) are expressed in several cell types, while receptors for IL-22 and IL-26 are expressed solely by epithelial cells [45–48]. Little is known about the role of IL-26 because this cytokine is not present in the mouse genome. In vitro stimulation of intestinal epithelial cells with IL-17, IL-22, or IL-26 induces changes in gene expression, including upregulation of chemokines (CXCL-8, CCL20) and antimicrobial responses (iNos, lipocalin-2) [49–52]. IL-17 also contributes to tight J Clin Immunol (2010) 30:196–203 junction formation and increased trans-epithelial resistance in polarized intestinal epithelial cells [53]. Both IL-17 and IL- 22 stimulate granulopoiesis by inducing expression of the granulocyte colony stimulating factor G-CSF [54–58]. Induction of G-CSF and CXC chemokine expression contribute to neutrophil accumulation and function in the mucosa in response to infection [59, 60]. Th17 cytokines thus contribute to the mucosal barrier by several mechanisms which, upon activation, result in a mucosal immune response geared towards eliminating pathogens. The mucosal response in patients with inflammatory diarrhea is characterized by a massive neutrophil infiltrate in the intestinal mucosa. Clinical evidence suggests that neu- trophils are important in containing diarrheal pathogens to the gut and preventing their systemic spread. In patients affected by primary neutrophil immunodeficiency (i.e., chronic gran- ulomatous disease), S. typhimurium often disseminates from the gut, resulting in bacteremia [61, 62]. HIV infection also results in a secondary neutrophil immunodeficiency [63, 64] which is likely a contributing factor to the susceptibility of HIV patients to bacteremia [65]. In the mouse model of inflammatory diarrhea, Th17 deficiency results in reduced neutrophil recruitment to the mucosa during infection with S. typhimurium [36]. Thus, a defect in neutrophil recruitment may explain why S. typhimurium dissemination increases in the absence of IL-17 signaling. One of the mucosal responses induced during C. rodentium colonic infection is the secretion of antimicrobial C-type lectins of the RegIII family, including Reg3γ and Reg3β [34]. Induction of Reg3γ is dependent on IL-22 and is important in controlling intestinal infection with C. rodentium or vancomycin-resistant enterococci [34, 66]. β-defensin 1, 3, and 4 are also induced during C. rodentium infection in the gut by IL-17A and IL-17F [43], however the role these antimicrobial peptides play in this model is not yet known. Gut Inflammation Promotes Pathogen Colonization Intestinal pathogens replicate in the gut and reach high numbers in the stool in order to achieve transmission via the fecal–oral route. Replication in the gut requires adaptation to harsh conditions including the presence of bile salts, mucus, and the resident microbiota competing for nutrients and binding sites along the intestinal epithelium. Several recent studies suggest that pathogens have an advantage over the resident microbiota in colonizing the gut as both C. rodentium and S. typhimurium infections lead to overgrowth of the pathogen with concomitant growth suppression of the resident microbiota [67–70]. However, such suppression occurs only in the presence of an inflammatory response, so in the absence of inflammation, the microbiota constitute a barrier against S. typhimurium colonization [67, 68]. While