J Clin Immunol (2010) 30:196–203 Orchestrating the Gut Mucosal Barrier: an Emerging Role for T Cells The host innate immune system is activated by pathogen- associated molecular patterns such as lipopolysaccharide and flagellin [7]. Epithelial cells, macrophages, and dendritic cells play an important role in the initial response to mucosal pathogens. However, there is mounting evi- dence that direct interaction of pathogens with these cells is not sufficient to generate an effective mucosal response. Resident T cells represent a major component of the gut mucosa and are located in between epithelial cells (intra- epithelial lymphocytes) and in the lamina propria [8]. It is the intraepithelial lymphocytes that likely contribute to the barrier function and integrity of the intestinal epithelium [9, 10]. Several subsets of T cells (αβ, γδ, NK, NK-T) are present in the gut mucosa and play an important role in mucosal immunity [11]. Perhaps the most striking evidence of the role T cells play in mucosal immunity comes from patients infected with the human immunodeficiency virus (HIV). HIV infects CD4+ T cells in the gut as early as a few weeks after infection, resulting in almost complete loss of this cell population [12–14]. Loss of mucosal CD4+ T-helper cells consequently results in a loss of function of both B cells and CD8+ T cells [15]. In HIV patients, CD4+ T cell depletion results in increased susceptibility to bacteremia caused by intestinal pathogens (mostly Salmonella, but also Shigella and Campylobacter) [16–18]. This indicates that CD4+ T cells are essential for the mucosal barrier against pathogens that normally cause inflammatory diarrhea. In the mouse model, depletion of either CD4+ or CD8+ T cell subsets results in increased translocation of E. coli to the mesenteric lymph nodes [19]. While mice do not develop inflammatory diarrhea when infected with S. typhimurium, streptomycin-pretreated mice infected with S. typhimurium develop an acute inflammatory response in the cecum [20]. In this model, CD3+ (T cell) depletion results in dramatic reduction of the gross pathology, neutrophil influx, and expression of pro-inflammatory cytokines and chemokines [21]. Similarly, CD3+ depletion or the absence of αβ T cells both result in reduced clearance of C. rodentium infection in mice [22, 23]. Overall, both clinical and experimental evidence reveal that mucosal T cells play an important role in containing commensals and pathogens to the gut. Th17 Cells Orchestrate the Mucosal Response to Gut Pathogens Several studies have suggested that a new subset of T cells, termed T-helper 17 (Th17) cells, orchestrate the mucosal defense against pathogens. Th17 cells constitute a distinct lineage from Th1 and Th2 cells and are characterized by the 197 production of a subset of cytokines: IL-17A, IL-17F, IL-22, and IL-26 [24]. Th17 cell differentiation is directed by the transcription factor RORγt, which is specific for the Th17 lineage [25]. The pro-inflammatory cytokines interleukin (IL)-6 and TGF-β appear to drive Th17 differentiation, at least in the mouse model [26], while the cytokine IL-23 appears to be indispensable for the protective effect of the Th17 response against mucosal pathogens like C. rodentium, Klebsiella pneumoniae, and S. typhimurium [27–29]. Another layer of complexity to the mucosal response to pathogens is that Th17 cytokines can be secreted by other cell types. IL-17 is released by γδ T cells in response to IL-23 stimulation [30, 31]. NK and NK-T cells can produce IL-17 and IL-22 [32, 33]. Antigen-presenting cells such as dendritic cells can secrete IL-22 in response to bacterial infection [34]. The cytokines IL-17A, IL-17F, and IL-22 are expressed in the mucosa in response to several bacterial and fungal pathogens; examples include K. pneumoniae infection in the lung, C. rodentium and S. typhimurium infection in the gut, Candida albicans infection of the oral cavity, and many others (reviewed in [35]). Adaptive T cells (Th17 cells), innate-like T cells (γδ T cells), or both can contribute to the host mucosal immune response. The contribution of Th17 cells during C. rodentium infection is evident during the second week post-infection [27]. In contrast, IL-17 expression occurs quite early during S. typhimurium infection, ranging from 5 h post-inoculation of rhesus macaque ileal loops to 48 h post-oral infection in mice [29, 36]. The vast majority of gut T cells in the aforemen- tioned rhesus macaque study were either CD4+ or CD8+ with γδ T cells comprising less than 1% of the total gut T cell population; this result suggests that γδ T cells are not a major source of IL-17 at 5 h post-S. typhimurium infection in adult rhesus macaques. In line with this observation, IL-17 production in response to S. typhimurium infection was dramatically decreased in macaques previously infected with the simian immunodeficiency virus which causes a selective loss of CD4+ T cells in the gut (comprising both Th1 and Th17 cells) [36]. In the mouse model, γδ T cells contributed to the IL-17 produced at day 2 post-infection, but they were not the sole source [29]. It thus appears that early activation of both adaptive and innate-like T cells can lead to expression of IL-17 and IL-22. As these T cells express the IL-23 receptor, expression of IL-23 by dendritic cells comprises a common trigger or potentiating factor for early T cell activation prior to the development of adaptive immunity. Th17 Development in the Gut Depends on Microbiota Composition The gut microbiota is primarily composed of bacteria belonging to the phyla Bacteroidetes and Firmicutes [37,