Appropriate regulation of gut immunity thus depends upon a complex three-way interplay between host cells, commensals and pathogens, and can exert a major impact on systemic responses including allergy and autoimmunity. In the gastrointestinal (GI) tract, the immune GW-572016 clinical trial system is faced with the most demanding of all decision-making, with little room for error. It is imperative at all times to discriminate between, and respond correctly to, beneficial symbionts, harmless food antigens and potential pathogens [1]. There is increasing appreciation that regulatory T cells (Tregs)

play a prominent and essential role in maintaining appropriate responsiveness in the gut [2,3], actively enforcing homeostasis and preventing untoward immune responses occurring. While stimulated by specific antigens, of both self and non-self origin, Tregs can transcend antigen specificity, mediating bystander suppression in a manner likely to modify systemic immune status as suggested by the ‘hygiene hypothesis’. Recent studies have changed our perspective of commensal microbes from benign but inert passengers to active participants in both the postnatal development of mucosal immunity and in its long-term steady-state function. Germ-free mice show extensive deficiencies

in intestinal immune system development, with reduced lymphoid tissue and fewer Acalabrutinib in vivo lymphocytes [4]. The CD4+ T cell population is diminished, affecting T helper type 1 (Th1) cells disproportionately although, remarkably, Treg frequencies are maintained or increased in germ-free mice. These and other data have established that defined components of the gut flora can play a major role in intestinal homeostasis, including protection against gut injury and mediating oral tolerance against dietary

antigens. ADP ribosylation factor In mice which acquire a conventional microbiome, the immune system develops normally while maintaining a continuing dialogue with the commensal population. Here, one of the dominant roles of Tregs is to prevent exuberant responses against gut flora, with which the intestinal tract is in intimate contact. Nevertheless, how commensals communicate with cells to ensure immune homeostasis is still unclear. One critical factor in this interaction at the molecular level is the host Toll-like receptor (TLR) system, as demonstrated by spontaneous colitis in TLR-5-deficient mice [5]. Where colitis is induced experimentally (e.g. by dextran sulphate administration), the absence of TLR signalling then results in greatly aggravated pathology, again indicating that TLR-mediated recognition of commensal molecules contributes to dampening immune reactivity [6]. The requirement for TLR signalling in induction of oral tolerance to dietary antigens [7] also speaks to the bimodal participation of the TLR system in both stimulatory and regulatory arms of the immune response. Recent evidence suggests that TLR signalling can impact Treg homeostasis and that Tregs themselves express TLRs selectively.