Our immune system usually ignores 'friendly' gut bacteria. But when infection with a pathogen damages the intestine's mucosal lining, the resident microbes can invade the body, inducing immune responses directed at themselves.
The mammalian gastrointestinal tract harbours an extensive microbial community that is usually well tolerated by the immune system. Sometimes, however, inappropriate immune responses directed against these 'commensal' organisms arise, such as in inflammatory bowel disease. But how such responses are triggered is unclear. Writing in Science, Hand et al.1 demonstrate that pathogenic infections that disrupt the integrity of the gut's mucosal barriers can precipitate the development of long-lived immunity directed against the host's resident microbes.
CD4+ T cells are a class of immune cell that deploys potent effector functions to combat infections. During development, a repertoire of T cells is generated such that there will be low numbers of cells specific for any given antigen — a substance that stimulates responses from T and B cells of the immune system. 'Naive' T cells are those that have not yet encountered the antigen for which their own antigen receptor is specific. Infection with a pathogen stimulates proliferation of pathogen-specific T cells, which not only increases the number of these cells, but also causes their differentiation to effector cells. As the proliferative response is ending, a population of long-lived pathogen-specific 'memory' cells is established, which provides a heightened state of readiness to respond to repeat infections. The signals received from different microbes cause the responding CD4+ T cells to adopt effector functions best suited to controlling the infection2. However, if a naive T cell encounters its specific antigen in the absence of infection, it is rendered 'tolerant', preventing a misdirected immune response. Thus, the context of initial antigen exposure is pivotal in determining T-cell behaviour.
Hand et al. examined CD4+ T cells specific for the flagellin protein expressed by certain Clostridium bacteria that are commensals in the gut lumen of adult mice (Fig. 1). They found that these non-pathogenic organisms are typically ignored by T cells, which remain in their naive state. However, when the researchers infected the mice with the parasitic protozoan Toxoplasma gondii, which causes intestinal damage, the clostridia breached the mucosal barrier and could be recovered from lymphoid organs such as lymph nodes and spleen. This translocation of the commensal bacteria caused naive Clostridium-flagellin-specific CD4+ T cells residing in lymphoid organs to proliferate and migrate to the gut.
Interestingly, as the Clostridium-specific T cells proliferated, they differentiated into effector T cells in a manner that mimicked the CD4+ T-cell response to T. gondii. They upregulated expression of T-bet, a gene-regulatory protein, and they acquired the ability to produce the cell-signalling molecule interferon-γ. These behaviours are characteristic of the Th1 differentiation state, which is associated with immune responses to intracellular infections but has also been implicated in numerous autoimmune diseases. Hand and colleagues also show that the mice retained a population of flagellin-specific memory CD4+ T cells long after resolution of the T. gondii infection and re-formation of the mucosal barrier.
These results have several interesting ramifications. For instance, inflammatory bowel disease (IBD), which includes Crohn's disease and ulcerative colitis, is characterized by aberrant CD4+ T-cell responses directed against intestinal commensal bacteria3. Although it is not clear how and why these responses are initiated, it is known that variations in several genes, including ones that regulate the immune response to gut bacteria and maintenance of the mucosal barrier, are tightly linked to IBD incidence4. However, identical twins with equal genetic susceptibility to IBD do not always both experience disease, which suggests a critical role for environmental triggers in this condition5.
Hand et al. provide evidence that exposure to pathogenic microbes could provide such a trigger. First, their results demonstrate that CD4+ T-cell ignorance of commensal bacteria can be broken during an infection, probably because of the increased amount of microbial antigen that is available to stimulate the immune system. Second, they show that pathogenic infections shape the differentiation program of contemporaneous commensal-specific CD4+ T-cell responses. In other words, when the commensal-specific CD4+ T cells are first activated, it is in the context of infection, and so they adopt an effector program that is dictated by the offending pathogen rather than by the resident gut microbes.
This differentiation program is distinct from that seen in experimental situations in which CD4+ T cells are exposed to commensal microbes in the absence of pathogenic infection6,7,8,9. It will be interesting to examine the relationship between various infections and the development of IBD-like disease in genetically predisposed mouse models. This is likely to be a fruitful line of enquiry, because a recent study has shown that infection of genetically susceptible mice with murine norovirus tipped the balance towards Crohn's-like disease symptoms10.
Hand and colleagues' study also emphasizes the fact that memory CD4+ T cells specific for commensal microbes may exist. The memory T-cell population studied by the authors, which was specific for a single peptide from Clostridium, was fairly small. However, when one considers that more than 3 million non-redundant genes have been identified11 in the human intestinal microbiome (all the microorganisms in the gut), this raises the question of whether a substantial fraction of all memory CD4+ T cells may actually be directed against commensal microbes. If this is the case, it would be particularly interesting to examine the effect of these cells on immune responses to subsequent intestinal infections (either with the same pathogen or one not previously encountered) that also cause disruptions of the mucosal barrier. It is conceivable that the commensal-specific memory CD4+ T cells have a protective capacity, by amplifying immunological sensing of barrier disruption. However, a commensal-reactive immune T-cell population could also contribute to inflammatory or autoimmune diseases of tissues exposed to such microbes, which include the skin and upper respiratory tract.
Thus, in addition to illuminating a potential mechanism underlying inflammatory conditions such as IBD, Hand and colleagues' findings indicate a potential limitation of the 'specific-pathogen-free' mouse model in which most basic immunological experiments are conducted. Such mice are not typically exposed to gut infections that compromise barrier integrity. This point provocatively suggests that, when studying immune responses to pathogens or commensal organisms, immunologists should also consider examining mice that have experienced past intestinal infections, because such infections could have a lasting impact on the immune system and might better recapitulate the human condition.
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