Mammals harbor a dense commensal microbiota in the colon. Regulatory T (Treg) cells are known to limit microbe-triggered intestinal inflammation and the CD4
+ T cell compartment is shaped by the ...presence of particular microbes or bacterial compounds. It is, however, difficult to distinguish whether these effects reflect true mutualistic immune adaptation to intestinal colonization or rather idiosyncratic immune responses. To investigate truly mutualistic CD4
+ T cell adaptation, we used the altered Schaedler flora (ASF). Intestinal colonization resulted in activation and de novo generation of colonic Treg cells. Failure to activate Treg cells resulted in the induction of T helper 17 (Th17) and Th1 cell responses, which was reversed by wild-type Treg cells. Efficient Treg cell induction was also required to maintain intestinal homeostasis upon dextran sulfate sodium-mediated damage in the colon. Thus, microbiota colonization-induced Treg cell responses are a fundamental intrinsic mechanism to induce and maintain host-intestinal microbial T cell mutualism.
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► Intestinal Treg cells are induced and activated by benign commensal colonization ► Activation of intestinal Treg cells is required for successful CD4
+ T cell homeostasis ► Treg cell activation is intrinsic and not due to differences in the flora composition ► Maintenance of homeostasis also requires Treg cell activation
Abstract The large production of immunoglobulin (Ig)A is energetically costly. The fact that evolution retained this apparent luxury of intestinal class switch recombination to IgA within the human ...population strongly indicates that there must be a critical specific function of IgA for survival of the species. The function of IgA has been investigated in a series of different models that will be discussed here. While IgA has clear protective functions against toxins or in the context of intestinal viral infections, the function of IgA specific for non-pathogenic commensal bacteria remains unclear. In the context of the current literature we present a hypothesis where secretory IgA integrates as an additional layer of immune function into the continuum of intestinal CD4 T cell responses, to achieve a mutualistic relationship between the intestinal commensal microbiota and the host.
IgE induction by parasites and allergens is antigen driven and cognate T cell help dependent. We demonstrate that spontaneously produced IgE in T cell-deficient and germ-free wild-type (wt) mice is ...composed of natural specificities and induced by a mechanism independent of MHC class II (MHC II) cognate help. This does not require secondary lymphoid structures or germinal center formation, although some bystander T cell-derived IL-4 is necessary. The pathway of spontaneous IgE production is not inhibited by regulatory T cells and increases with age to constitute significant serum concentrations, even in naive animals.
Thymic stromal lymphopoietin (TSLP) is constitutively expressed in the intestine and is known to regulate inflammation in models of colitis. We show that steady-state TSLP expression requires ...intestinal bacteria and has an important role in limiting the expansion of colonic T helper type 17 (Th17) cells. Inappropriate expansion of the colonic Th17 cells occurred in response to an entirely benign intestinal microbiota, as determined following the colonization of germ-free C57BL/6 or TSLPR(-/-) mice with the altered Schaedler flora (ASF). TSLP-TSLPR (TSLP receptor) interactions also promoted the expansion of colonic Helios(-)Foxp3(+) regulatory T cells, necessary for the control of inappropriate Th17 responses following ASF bacterial colonization. In summary, these data reveal an important role for TSLP-TSLPR signaling in promoting steady-state mutualistic T-cell responses following intestinal bacterial colonization.
Summary
Animals contain an enormous load of non‐pathogenic bacteria in the lower intestine, which exploit an environment with a stable temperature and abundant carbon sources. Our load of bacteria ...outnumbers our own cells. In order to survive with such a high number of organisms in very close proximity to host tissues the intestinal mucosa and its immune system is highly adapted. Mucosal immune responses are induced by small numbers of live commensal organisms penetrating the Peyer's patches and persisting in dendritic cells (DC). These DC can induce immunoglobulin A+ (IgA+) B cells, which recirculate through the lymph and bloodstream to populate the lamina propria and secrete protective IgA. Because DC loaded with commensal bacteria do not penetrate further than the mesenteric lymph nodes, immune induction to commensals is confined to the mucosa, allowing strong mucosal immune responses to be induced whilst the systemic immune system remains relatively ignorant of these organisms.
Myocarditis can develop into inflammatory cardiomyopathy through chronic stimulation of myosin heavy chain 6-specific T helper (T
)1 and T
17 cells. However, mechanisms governing the cardiotoxicity ...programming of heart-specific T cells have remained elusive. Using a mouse model of spontaneous autoimmune myocarditis, we show that progression of myocarditis to lethal heart disease depends on cardiac myosin-specific T
17 cells imprinted in the intestine by a commensal
species peptide mimic. Both the successful prevention of lethal disease in mice by antibiotic therapy and the significantly elevated
specific CD4
T cell and B cell responses observed in human myocarditis patients suggest that mimic peptides from commensal bacteria can promote inflammatory cardiomyopathy in genetically susceptible individuals. The ability to restrain cardiotoxic T cells through manipulation of the microbiome thereby transforms inflammatory cardiomyopathy into a targetable disease.
Neutropenia is probably the strongest known predisposition to infection with otherwise harmless environmental or microbiota-derived species. Because initial swarming of neutrophils at the site of ...infection occurs within minutes, rather than the hours required to induce "emergency granulopoiesis," the relevance of having high numbers of these cells available at any one time is obvious. We observed that germ-free (GF) animals show delayed clearance of an apathogenic bacterium after systemic challenge. In this article, we show that the size of the bone marrow myeloid cell pool correlates strongly with the complexity of the intestinal microbiota. The effect of colonization can be recapitulated by transferring sterile heat-treated serum from colonized mice into GF wild-type mice. TLR signaling was essential for microbiota-driven myelopoiesis, as microbiota colonization or transferring serum from colonized animals had no effect in GF MyD88(-/-)TICAM1(-/-) mice. Amplification of myelopoiesis occurred in the absence of microbiota-specific IgG production. Thus, very low concentrations of microbial Ags and TLR ligands, well below the threshold required for induction of adaptive immunity, sets the bone marrow myeloid cell pool size. Coevolution of mammals with their microbiota has probably led to a reliance on microbiota-derived signals to provide tonic stimulation to the systemic innate immune system and to maintain vigilance to infection. This suggests that microbiota changes observed in dysbiosis, obesity, or antibiotic therapy may affect the cross talk between hematopoiesis and the microbiota, potentially exacerbating inflammatory or infectious states in the host.
Rare cases of stable allograft acceptance after discontinuation of immunosuppression are often accompanied by macrochimerism (> 1% donor cells in blood) or microchimerism (< 1% donor cells in blood). ...Here, we have investigated whether persistence of donor cells is the cause or the consequence of long-lasting CTL unresponsiveness. We found that engraftment of splenocytes bearing a single foreign MHC class I-restricted epitope resulted in lifelong donor cell microchimerism and specific CTL unresponsiveness. This status was reversed in a strictly time- and thymus-dependent fashion when the engrafted cells were experimentally removed. The results presented herein show that microchimerism actively maintains CTL unresponsiveness toward a minor histocompatibility antigen by deleting the specific repertoire and thus excluding dominant, T cell extrinsic mechanisms of CTL unresponsiveness independent of systemically persisting donor cell antigen.
Abstract
Background
Inflammatory bowel diseases (IBD) are chronic inflammatory disorders of the gastrointestinal tract. Despite achieving endoscopic remission, up to 50% of IBD patients continue to ...experience chronic abdominal pain, with female patients displaying an increased prevalence. The reason underlying these differences in pain perception is unknown, but the influence of sex hormones represents an important biological source for variability in pain sensitivity. To date, few studies have examined sex differences in chronic visceral pain in IBD.
Purpose
Examine sex-specific differences in post-inflammatory chronic visceral pain in IBD.
Method
We used the post-inflammatory DSS mouse model of chronic visceral pain. Ovariectomy was performed to study the effects of estrogen deficiency; sham surgery was performed as a control. Male, cycling female and ovariectomized female mice were given 2.5% DSS for five days and allowed to recover for 5 weeks. Somatic pain was evaluated using the hot plate and von Frey hair tests. Visceral pain was evaluated using the visceral motor reflex (VMR) to colorectal distension five weeks after DSS treatment. Visceral and somatic pain testing in cycling females was performed in diestrus.
Result(s)
Male, cycling female and ovariectomized female mice given DSS initially lost weight when compared to controls (p<0.0001). Cycling females displayed significantly decreased colitis severity when compared to males Disease Activity Index at Day 12: 1.41 ± 0.41 cycling females, n=12; 4.41 ± 0.31 males, n=12; p<0.001 but increased severity compared to ovariectomized females Disease Activity Index at Day 12: 2.0 ± 0.41 ovariectomized females, n=13; 4.77 ± 0.6 cycling females, n=13, p=0.0005. Increased visceral hypersensitivity was seen in post-inflammatory cycling females compared to post-inflammatory males VMR at 60mmHg, post-inflammatory cycling females 0.10 ± 0.016, n=10; post-inflammatory males 0.07 ± 0.007, n=10; p=0.032 and post-inflammatory ovariectomized females VMR at 60mmHg, post-inflammatory sham females 0.072 ± 0.005, n=8; post-inflammatory ovariectomized females 0.047 ± 0.005, n=8; p=0.019. Thermal hyperalgesia and mechanical allodynia were similar across all groups.
Conclusion(s)
These data suggest that estrogen plays an important role in the severity of colitis severity and post-inflammatory visceral pain. Understanding sex-specific differences in post-inflammatory visceral pain in IBD may allow us to define novel therapeutic approaches for IBD patients.
Disclosure of Interest
None Declared
Retroviruses have the potential to acquire host cell-derived genetic material during reverse transcription and can integrate into the genomes of larger, more complex DNA viruses. In contrast, RNA ...viruses were believed not to integrate into the host's genome under any circumstances. We found that illegitimate recombination between an exogenous nonretroviral RNA virus, lymphocytic choriomeningitis virus, and the endogenous intracisternal A-type particle (IAP) retrotransposon occurred and led to reverse transcription of exogenous viral RNA. The resulting complementary DNA was integrated into the host's genome with an IAP element. Thus, RNA viruses should be closely scrutinized for any capacity to interact with endogenous retroviral elements before their approval for therapeutic use in humans.
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