The link between Tregs and the ‘hygiene hypothesis’ is discussed in detail elsewhere in this workshop. In principle, stimulation of the T cell system via microbial-derived signals GPCR Compound Library clinical trial emanating principally from the GIT may be one route via which functionally mature Tregs are generated, and these cells may contribute to maintenance of homeostasis in peripheral tissues distal to the GIT. In early life, one source of such Tregs may be recent thymic emigrant (RTE) CD4+ T cells. Human in vitro studies from

our group and others [16,45,47], echoing earlier work in the mouse [48], have demonstrated that naive RTE which dominate the circulating CD4+ T cell compartment during infancy respond ‘non-specifically’ to peptides, leading to rapid activation and cytokine production which is usually terminated soon thereafter by apoptotic death. However, a subset of these RTE survive and potentially may thus enter the recirculating T cell compartment [16,47]. These survivors acquire Treg Ulixertinib price activity during the activation process [16]; this process may reflect events occurring in the lymphoid drainage of the GIT under the influence of microbial-derived antigens, providing a continuous ‘drip-feed’ of functionally activated Tregs. The de novo generation

and/or boosting of existing Treg activity by controlled microbial stimulation of the GIT is one of the aims of probiotic therapies which are being tested in many centres internationally, but there are few direct data available to confirm the efficient operation of this mechanism in humans. However, recent mouse data support the potential feasibility of this approach. In particular, gavage of mice with a bolus of live Lactobacillus reuteri increases numbers and functional activity of

Tregs in central lymphoid organs [49]. Moreover, if this is carried out in sensitized animals prior to aeroallergen challenge, ensuing lung eosinophilia and airways hyperresponsiveness is attenuated significantly and this effect can 2-hydroxyphytanoyl-CoA lyase be reproduced by adoptive transfer of Tregs harvested from spleens of L. reuteri-gavaged animals [49]. We have obtained similar findings in a rat atopic asthma model employing repeated feeding with a microbial extract containing multiple TLR ligands, and moreover we have observed that the attenuation of aeroallergen-induced airways inflammatory responses in prefed animals is associated with increased baseline numbers of Tregs in the airway mucosa (to be published). These latter findings suggest that one of the principle tenets of the ‘common mucosal immune system’ concept, notably that adaptive immune cell populations activated in the GIT mucosa will subsequently traffic preferentially to other mucosal sites, may be exploitable in relation to therapeutic control of allergy-induced lung inflammation.