RESUMEN
Healthy host-microbial mutualism with our intestinal microbiota relies to a large degree on compartmentalization and careful regulation of adaptive mucosal and systemic anti-microbial immune responses. However, commensal intestinal bacteria are never exclusively or permanently restricted to the intestinal lumen and regularly reach the systemic circulation. This results in various degrees of commensal bacteremia that needs to be appropriately dealt with by the systemic immune system. While most intestinal commensal bacteria, except for pathobionts or opportunistic pathogen, have evolved to be non-pathogenic, this does not mean that they are non-immunogenic. Mucosal immune adaptation is carefully controlled and regulated to avoid an inflammatory response, but the systemic immune system usually responds differently and more vigorously to systemic bacteremia. Here we show that germ-free mice have increased systemic immune sensitivity and display anti-commensal hyperreactivity in response to the addition of a single defined T helper cell epitope to the outer membrane porin C (OmpC) of a commensal Escherichia coli strain demonstrated by increased E. coli-specific T cell-dependent IgG responses following systemic priming. This increased systemic immune sensitivity was not observed in mice colonized with a defined microbiota at birth indicating that intestinal commensal colonization also regulates systemic, and not only mucosal, anti-commensal responses. The observed increased immunogenicity of the E. coli strain with the modified OmpC protein was not due to a loss of function and associated metabolic changes as a control E. coli strain without OmpC did not display increased immunogenicity.
Asunto(s)
Bacteriemia , Escherichia coli , Animales , Ratones , Mucosa Intestinal , Simbiosis , Intestinos , Bacteriemia/patologíaRESUMEN
The intestine harbors a large population of resident eosinophils, yet the function of intestinal eosinophils has not been explored. Flow cytometry and whole-mount imaging identified eosinophils residing in the lamina propria along the length of the intestine prior to postnatal microbial colonization. Microscopy, transcriptomic analysis, and mass spectrometry of intestinal tissue revealed villus blunting, altered extracellular matrix, decreased epithelial cell turnover, increased gastrointestinal motility, and decreased lipid absorption in eosinophil-deficient mice. Mechanistically, intestinal epithelial cells released IL-33 in a microbiota-dependent manner, which led to eosinophil activation. The colonization of germ-free mice demonstrated that eosinophil activation in response to microbes regulated villous size alterations, macrophage maturation, epithelial barrier integrity, and intestinal transit. Collectively, our findings demonstrate a critical role for eosinophils in facilitating the mutualistic interactions between the host and microbiota and provide a rationale for the functional significance of their early life recruitment in the small intestine.
Asunto(s)
Enfermedades Transmisibles , Microbiota , Animales , Eosinófilos , Homeostasis , Mucosa Intestinal , Intestino Delgado , RatonesRESUMEN
Several species of intestinal bacteria have been associated with enhanced efficacy of checkpoint blockade immunotherapy, but the underlying mechanisms by which the microbiome enhances antitumor immunity are unclear. In this study, we isolated three bacterial species-Bifidobacterium pseudolongum, Lactobacillus johnsonii, and Olsenella species-that significantly enhanced efficacy of immune checkpoint inhibitors in four mouse models of cancer. We found that intestinal B. pseudolongum modulated enhanced immunotherapy response through production of the metabolite inosine. Decreased gut barrier function induced by immunotherapy increased systemic translocation of inosine and activated antitumor T cells. The effect of inosine was dependent on T cell expression of the adenosine A2A receptor and required costimulation. Collectively, our study identifies a previously unknown microbial metabolite immune pathway activated by immunotherapy that may be exploited to develop microbial-based adjuvant therapies.
Asunto(s)
Bifidobacterium/metabolismo , Microbioma Gastrointestinal , Inmunoterapia , Inosina/metabolismo , Neoplasias Intestinales/terapia , Lactobacillus johnsonii/metabolismo , Melanoma/terapia , Neoplasias Cutáneas/terapia , Neoplasias de la Vejiga Urinaria/terapia , Animales , Anticuerpos/uso terapéutico , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/inmunología , Antígeno CTLA-4/antagonistas & inhibidores , Antígeno CTLA-4/inmunología , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Neoplasias Experimentales/terapia , Receptor de Adenosina A2A/metabolismo , Linfocitos T/inmunologíaRESUMEN
Eradication of pathogens from the bloodstream is critical to prevent disseminated infections and sepsis. Kupffer cells in the liver form an intravascular firewall that captures and clears pathogens from the blood. Here, we show that the catching and killing of circulating pathogens by Kupffer cells in vivo are promoted by the gut microbiota through commensal-derived D-lactate that reaches the liver via the portal vein. The integrity of this Kupffer cell-mediated intravascular firewall requires continuous crosstalk with gut commensals, as microbiota depletion with antibiotics leads to a failure of pathogen clearance and overwhelming disseminated infection. Furthermore, administration of purified D-lactate to germ-free mice, or gnotobiotic colonization with D-lactate-producing commensals, restores Kupffer cell-mediated pathogen clearance by the liver firewall. Thus, the gut microbiota programs an intravascular immune firewall that protects against the spread of bacterial infections via the bloodstream.
Asunto(s)
Antibacterianos/farmacología , Infecciones Bacterianas/tratamiento farmacológico , Microbioma Gastrointestinal/inmunología , Sustancias Protectoras/farmacología , Animales , Bacterias , Infecciones Bacterianas/microbiología , Disbiosis , Vida Libre de Gérmenes , Macrófagos del Hígado , Lactobacillus , Hígado/microbiología , Ratones , Ratones Endogámicos C57BL , Sepsis , Staphylococcus aureus , SimbiosisRESUMEN
Induction of intestinal T helper cell subsets by commensal members of the intestinal microbiota is an important component of the many immune adaptations required to establish host-microbial homeostasis. Importantly, altered intestinal T helper cell profiles can have pathological consequences that are not limited to intestinal sites. Therefore, microbial-mediated modulation of the intestinal T helper cell profile could have strong therapeutic potentials. However, in order to develop microbial therapies that specifically induce the desired alterations in the intestinal T helper cell compartment one has to first gain a detailed understanding of how microbial composition and the metabolites derived or induced by the microbiota impact on intestinal T helper cell responses. Here we summarize the milestone findings in the field of microbiota-intestinal T helper cell crosstalk with a focus on the role of specific commensal bacteria and their metabolites. We discuss mechanistic mouse studies and are linking these to human studies where possible. Moreover, we highlight recent advances in the field of microbial CD4 T cell epitope mimicry in autoimmune diseases and the role of microbially-induced CD4 T cells in cancer immune checkpoint blockade therapy.
Asunto(s)
Enfermedades Autoinmunes/inmunología , Microbioma Gastrointestinal/inmunología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Mucosa Intestinal/inmunología , Intestinos/inmunología , Neoplasias/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Animales , Epítopos/inmunología , Homeostasis , Humanos , Ratones , Imitación Molecular , Neoplasias/terapiaRESUMEN
The microbiota plays an important role in regulating both the innate and adaptive immune systems. Many studies have focused on the ability of microbes to shape the immune system by stimulating B-cell and antibody responses and the differentiation of T helper cell function. However, an important feature of the immune system is its ability to generate memory responses, which provide increased survival for the host. This review will highlight the role of the microbiota in the induction of immune memory with a focus on both adaptive and innate memory as well as vaccine efficacy.
Asunto(s)
Inmunidad , Memoria Inmunológica , Inmunomodulación , Microbiota/inmunología , Animales , Anticuerpos/inmunología , Formación de Anticuerpos/inmunología , Microbioma Gastrointestinal/inmunología , Humanos , Inmunidad Innata , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Vacunas/inmunologíaRESUMEN
Macrophages play central roles in immunity as early effectors and modulating adaptive immune reponses; we implicated macrophages in the anticolitic effect of infection with the tapeworm Hymenolepis diminuta. Here, gene arrays revealed that H. diminuta antigen (HdAg) evoked a program in murine macrophages distinct from that elicited by IL-4. Further, HdAg suppressed LPS-evoked release of TNF-α and IL-1ß from macrophages via autocrine IL-10 signaling. In assessing the ability of macrophages treated in vitro with an extract of H. diminuta [M(HdAg)] to affect disease, intravenous, but not peritoneal, injection of M(HdAg) protected wild-type but not RAG1-/- mice from dinitrobenzene sulphonic acid (DNBS)-induced colitis. Administration of splenic CD4+ T cells from in vitro cocultures with M(HdAg), but not those cocultured with M(IL-4) cells, inhibited DNBS-induced colitis; fractionation of the T-cell population indicated that the CD4+CD25+ T cells from cocultures with M(HdAg) drove the suppression of DNBS-induced colitis. Use of IL-4-/- or IL-10-/- CD4+ T cells revealed that neither cytokine alone from the donor cells was essential for the anticolitic effect. These data illustrate that HdAg evokes a unique regulatory program in macrophages, identifies HdAg-evoked IL-10 suppression of macrophage activation, and reveals the ability of HdAg-treated macrophages to educate ( i.e., condition) and mobilize CD4+CD25+ T cells, which could be deployed to treat colonic inflammation.-Reyes, J. L., Lopes, F., Leung, G., Jayme, T. S., Matisz, C. E., Shute, A., Burkhard, R., Carneiro, M., Workentine, M. L., Wang, A., Petri, B., Beck, P. L., Geuking, M. B., McKay, D. M., Macrophages treated with antigen from the tapeworm Hymenolepis diminuta condition CD25+ T cells to suppress colitis.
Asunto(s)
Antígenos Helmínticos/inmunología , Linfocitos T CD4-Positivos/inmunología , Cestodos/inmunología , Colitis/inmunología , Hymenolepis diminuta/inmunología , Subunidad alfa del Receptor de Interleucina-2/inmunología , Macrófagos/inmunología , Animales , Colitis/parasitología , Colon/inmunología , Colon/parasitología , Citocinas/inmunología , Humanos , Interleucina-10/inmunología , Interleucina-4/inmunología , Activación de Macrófagos/inmunología , Macrófagos/parasitología , Masculino , Ratones , Ratones Endogámicos BALB CRESUMEN
Diffuse large B-cell lymphoma is the most common malignant lymphoma in adults. By gene-expression profiling, this lymphoma is divided in three cell-of-origin subtypes with distinct molecular and clinical features. Most lymphomas arise sporadically, yet familial clustering is known, suggesting a genetic contribution to disease risk. Familial lymphoma cases are a valuable tool to investigate risk genes. We studied a Swiss/Japanese family with 2 sisters affected by a primary mediastinal B-cell lymphoma and a non-germinal center diffuse large B-cell lymphoma not otherwise specified, respectively. The somatic landscape of both lymphomas was marked by alterations affecting multiple components of the JAK-STAT pathway. Consequently, this pathway was constitutively activated as evidenced by high pJAK2 as well as increased nuclear pSTAT3 and pSTAT6 in malignant cells. Potential lymphoma risk variants were identified by whole exome sequencing of the germline DNA derived from siblings and unaffected family members. This analysis revealed a pathogenic variant in TIRAP, an upstream regulator of NF-κB, in both affected siblings and their mother. We observed increased B-cell proliferation in family members harboring the TIRAP p.R81C variant. B-cell proliferation correlated with TIRAP and NF-κB target gene expression, suggesting enhanced NF-κB pathway activity in TIRAP p.R81C individuals. TIRAP knockdown reduced B-cell survival and NF-κB target gene expression, particularly in individuals with TIRAP p.R81C. Functional studies revealed significantly increased NF-κB activity and resistance to stress-induced cell-death by TIRAP p.R81C. The identification of an inherited TIRAP variant provides evidence for a novel link between genetic alterations affecting the NF-κB pathway and lymphomagenesis.
Asunto(s)
Linfocitos B , Proliferación Celular/genética , Linfoma de Células B Grandes Difuso , Neoplasias del Mediastino , Glicoproteínas de Membrana , Mutación Missense , Receptores de Interleucina-1 , Hermanos , Transducción de Señal/genética , Adulto , Linfocitos B/metabolismo , Linfocitos B/patología , Femenino , Humanos , Janus Quinasa 2/genética , Janus Quinasa 2/metabolismo , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/metabolismo , Linfoma de Células B Grandes Difuso/patología , Masculino , Neoplasias del Mediastino/genética , Neoplasias del Mediastino/metabolismo , Neoplasias del Mediastino/patología , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Receptores de Interleucina-1/genética , Receptores de Interleucina-1/metabolismo , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT6/genética , Factor de Transcripción STAT6/metabolismo , Secuenciación del ExomaRESUMEN
Females have an overall advantage over males in resisting Gram-negative bacteremias, thus hinting at sexual dimorphism of immunity during infections. Here, through intravital microscopy, we observed a sex-biased difference in the capture of blood-borne bacteria by liver macrophages, a process that is critical for the clearance of systemic infections. Complement opsonization was indispensable for the capture of enteropathogenic Escherichia coli (EPEC) in male mice; however, a faster complement component 3-independent process involving abundant preexisting antibodies to EPEC was detected in female mice. These antibodies were elicited predominantly in female mice at puberty in response to estrogen regardless of microbiota-colonization conditions. Estrogen-driven antibodies were maternally transferrable to offspring and conferred protection during infancy. These antibodies were conserved in humans and recognized specialized oligosaccharides integrated into the bacterial lipopolysaccharide and capsule. Thus, an estrogen-driven, innate antibody-mediated immunological strategy conferred protection to females and their offspring.
Asunto(s)
Anticuerpos Antibacterianos/inmunología , Infecciones por Escherichia coli/inmunología , Inmunidad Innata/inmunología , Caracteres Sexuales , Animales , Escherichia coli Enteropatógena , Estrógenos/inmunología , Femenino , Humanos , Lactante , Macrófagos del Hígado/inmunología , Masculino , Intercambio Materno-Fetal/inmunología , Ratones , EmbarazoRESUMEN
BCL2 is a target of somatic hypermutation in t(14;18) positive and also in a small fraction of t(14;18) negative diffuse large B-cell lymphoma (DLBCL), suggesting an aberrant role of somatic hypermutation (ASHM). To elucidate the prevalence of BCL2 mutations in lymphomas other than DLBCL, we Sanger-sequenced the hypermutable region of the BCL2 gene in a panel of 69 mature B-cell lymphomas, including Richter's syndrome DLBCL, marginal-zone lymphomas, post-transplant lymphoproliferative disorders, HIV-associated and common-variable immunodeficiency-associated DLBCL, all known to harbour ASHM-dependent mutations in other genes, as well as 16 t(14,18) negative and 21 t(14;18) positive follicular lymphomas (FLs). We also investigated the pattern of BCL2 mutations in longitudinal samples from 10 FL patients relapsing to FL or transforming to DLBCL (tFL). By direct sequencing, we found clonally represented BCL2 mutations in 2/16 (13%) of t(14;18) negative FLs, 2/16 (13%) HIV-DLBCLs, 1/9 (11%) of Richter's syndrome DLBCL, 1/17 (6%) of post-transplant lymphoproliferative disorders and 1/2 (50%) common-variable immunodeficiency-associated DLBCL. The proportion of mutated cases was significantly lower than in FLs carrying the t(14;18) translocation (15/21, 71%). However, the absence of t(14;18) by FISH or PCR and the molecular features of the mutations strongly suggest that BCL2 represents an additional target of ASHM in these entities. Analysis of the BCL2 mutation pattern in clonally related FL/FL and FL/tFL samples revealed two distinct scenarios of genomic evolution: (i) direct evolution from the antecedent FL clone, with few novel clonal mutations acquired by the tFL major clone, and (ii) evolution from a common mutated long-lived progenitor cell, which subsequently acquired distinct mutations in the FL and in the relapsed or transformed counterpart.