For a long time scientists have been puzzled by the fact that the immune system in the gut is capable of fighting toxic bacterial infection while staying, at the same time, tolerant to its resident “friendly” bacteria. But an article now published in the journal Cell Host & Microbe(1) is starting to open the door to this mystery by revealing how a recently discovered gene - pims – is activated by the gut immune response against friendly bacteria to rapidly suppress it, effectively creating tolerance to the gut microbiota. In the same way pims is also shown to control the magnitude of immune responses against toxic bacteria by suppressing immuno-reactivity when a certain activation threshold is achieved, assuring, in this way, that the response stays restricted to the infection site and is proportional to the extent of the infection. These results suggest that the balance tolerance/immuno-reaction in the gut is achieved through self-regulatory cycles where suppression by negative regulators, such as pims, is triggered as soon as a specific threshold of immuno activation is reached. This work has implications in the understanding of diseases in which the normal gut immune response is disrupted - such as Crohn's disease and ulcerative colitis – but, potentially, also in oral tolerance. In fact, oral tolerance vaccines - in which the molecule we want immuno-tolerated is ingested - have been tentatively used for the treatment of several autoimmune diseases (where the immune system abnormally attacks parts of the body) with mixed results and the new research, by elucidating the players in gut immuno-tolerance, might help to understand why. Multicellular animals live peacefully in close contact with a multitude of microorganisms that inhabit their bodies. Humans, for example, have more microorganisms within the body than cells, with just the intestine containing up to 100 trillion microbes, a number about 10 times greater that all our cells. Still, although we remain fully immune competent - so capable of responding to infection by pathogenic microorganisms - we do not react against these “friendly” bacteria. But how do these two opposite immune responses against bacteria so similar exist simultaneously? In order to understand better this phenomenon Nouara Lhocine, Paulo S. Ribeiro, Francois Leulier and colleagues working in France, London, Switzerland and Portugal used Drosophila (fruit fly) – a common animal model to study human gene functions due to the large numbers of genes shared by the two species - to investigate the possibility that a recently discovered gene – pims – could be involved in this coexistence of tolerance and immuno-reactivity. In fact, in the Drosophila gut, one of the main responses against bacterial infection is the Imd pathway. The activation of this immune pathway is triggered by peptidoglycans – sugars found on the bacterial wall – and results in the activation of a molecule called Relish. Once activated, Relish induces the expression of several antimicrobial genes to neutralize the invading pathogens. “Friendly” bacteria, on the other hand, despite containing peptidoglycans in their wall exist peacefully inside Drosophila’s gut. The newfound gene– pims – was shown to be expressed during bacterial infection in the gut while its inhibition apparently disrupted the Imd pathway suggesting a role in the regulation of this pathway. Lhocine, Ribeiro, Leulier and colleagues started by analysing pims expression in Drosophila to find it mainly expressed in the gut where it depends on the existence of “friendly” bacteria and activated Relish. These results further suggested – since a basal level of immune response is necessary for pims expression - that this gene acted on the immune response and, specifically, in the gut. The next step was to analyse what happened to this gut immune response in animals lacking pims. And it was found that, not only these animals showed an immune response against “friendly” bacteria, but also that, during toxic bacterial infection the immune response abnormally spread out of the site of infection risking body injury. These results reveal pims as a negative regulator of the immune response (Imd pathway) granting tolerance to “friendly” gut bacteria, but also assuring that immune responses against infection are contained to the site of infection. Although the exact mechanism of pims is not fully understood, Lhocine, Ribeiro, Leulier and colleagues were able to show that the peptide produced by pims binds a peptidoglycan receptor, part of the Imd pathway, called PGRP-LCx, . As PGRP-LCx recognition of peptidoglycans activates Imd and ultimately Relish, the outcome of the interaction with Pims is lack of availability to peptidoglycans and consequently suppression of the (Imd) immune response. Results from microscopic observation and separation of the cell’s soluble and insoluble components suggested, however, that PIMS acted, not by destroying PGRP-LCx but by misplacing it, away from its usual localisation – the plasma membrane – resulting in an incapability of the immune system to see peptidoglycans and consequently of getting activated. Lhocine, Ribeiro, Leulier and colleagues’ results suggest a model where pims is a negative immuno-regulator triggered when specific Imd activation thresholds are reached, after which the immune response is suppressed. It is the existence of this immuno-reactivity threshold that allows the simultaneous existence of tolerance to the gut microorganisms while maintaining immuno-reactivity against infection.. Since peptidoglycans are widely present in bacteria the next question would be to find if the regulatory system here described applies to other host-microorganisms interactions, including those involving humans. NOTES: (1) Nouara Lhocine, Paulo S. Ribeiro, Francois Leulier, “PIMS Modulates Immune Tolerance by Negatively Regulating Drosophila Innate Immune Signaling”, Cell Host & Microbe – Vol 4, 147-158 August