In increased activation of NF-?B signalling and

In close proximity to IECs, intestinal mononuclear phagocytes (iMP) –DCs and macrophages (M?) – are regarded as key players in the intestinal immune response, as they link innate and adaptive immunity. Intestinal DCs express several PRRs and secrete cytokines and chemokines upon stimulation. Consequently, they migrate to MLNs to promote adaptive immune responses, as well as oral tolerance.144 Gastrointestinal M?s maintain gut homeostasis as they are characterized by low production of pro-inflammatory mediators, but an intact phagocytic ability.145 In CD patients however, intestinal M? express high levels of co-stimulatory molecules, show increased activation of NF-?B signalling and oxidative burst activity. Furthermore, they have a high expression of TLR2 and TLR4, as well as an augmented secretion of cytokines, including TNF and IL-23.146-151. Intestinal DCs also induce regulatory adaptive immunity by factors such as TGF-beta, IL-10 and retinoic acid, thereby promoting forkhead box P3 (Foxp3)+ regulatory T cells (Treg).152 Commensals can also directly influence Foxp3+ Treg cell induction, through TLR2-interaction on T lymphocytes.153 Lathrop et al also showed, that Foxp3+ iTreg cells in the lamina propria express a unique subset of T cell receptors (TCRs) that recognised epitopes derived from the commensal microbiota. By manipulating the intestinal ecosystem via antibiotics, the TCR repertoire of colonic Foxp3+ Treg cells was altered.154-156 Also bacteria-derived short chain fatty acids (SCFA), particularly butyrate, can directly induce the differentiation of intestinal Foxp3+ iTreg.156-158 Hereby an interesting hypothesis is raised by Kabat et al.: Commensals also express pathogen associated molecular patterns (PAMPs), however the intestinal immune system is capable to distinguish pathogens from commensals. Therefore, microbial metabolites like SCFA may therefore serve as “surrogate for symbiosis”, enforcing a tolerant immune responses and intestinal homeostasis in the host.159 T cells also express PRRs that allow them to directly sense and respond to microbial patterns, as recently shown for ??-T cells, which are enriched in the intraepithelial lymphocyte population (IEL). TLR2-signalling on ??-T cells, potentiated Th17 differentiation and induction of effector cells.160 In CD patients, exacerbated Th1- and Th17-mediated immune responses are observed, along with detrimentally high levels of TNF?, IFN?, IL-17 and IL-22.161-164Another, recently discovered lineage of immune cells that postures a microbial influenced route of immune homeostasis are innate lymphoid cells (ILC). These innate leukocytes display lymphoid morphology but lack rearranged antigen receptors and are also phenotypically distinct from myeloid lineages.165 ILCs are enriched in mucosal tissues and were differentiated into three subgroups based on phenotypic and functional characteristics: ILC1 (T-bet+), ILC2 (GATA-binding protein 3 positive), and ILC3 (retinoic acid receptor-related orphan receptor-?t; ROR?t). ILC3 play an important role in immune homeostasis. Upon microbial stimulation, they are the major innate source of IL-22 in the lamina propria, and therefore limit systemic dissemination of commensals.166, 167 Subsequently, IL-22 signals through IL-22R on IECs, to activate signal transducer and activator of transcription 3 (STAT3) and induce AMPs, including Reg3? and Reg3?, that protect against enteric pathogens.168-170 ILCs are discussed to have an important role in CD development, as several studies showed increased ILC numbers in the lamina propria of CD patients, though their specific role in IBD still has to be unravelled.171-173As IBD development is a complex interaction of innate and adaptive immune cells towards commensal stimuli, the therapeutical modulation of the immune response and its microbial triggers is multifaceted and difficult. Due to the central role of the gut microbiota in pathology development, targeted modulation of the intestinal microbiota and the microbe-host interaction, may state an interesting new treatment approach.