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Susceptibility to respiratory virus infections (RVIs) varies widely across individuals. Because the gut microbiome impacts immune function, we investigated the influence of intestinal microbiota composition on RVI and determined that segmented filamentous bacteria (SFB), naturally acquired or exogenously administered, protected mice against influenza virus (IAV) infection. Such protection, which also applied to respiratory syncytial virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was independent of interferon and adaptive immunity but required basally resident alveolar macrophages (AMs). In SFB-negative mice, AMs were quickly depleted as RVI progressed. In contrast, AMs from SFB-colonized mice were intrinsically altered to resist IAV-induced depletion and inflammatory signaling. Yet, AMs from SFB-colonized mice were not quiescent. Rather, they directly disabled IAV via enhanced complement production and phagocytosis. Accordingly, transfer of SFB-transformed AMs into SFB-free hosts recapitulated SFB-mediated protection against IAV. These findings uncover complex interactions that mechanistically link the intestinal microbiota with AM functionality and RVI severity.
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Microbioma Gastrointestinal , Virosis , Animales , Ratones , Macrófagos Alveolares , Fagocitosis , Interferones , BacteriasRESUMEN
Susceptibility to respiratory virus infections (RVIs) varies widely across individuals. Because the gut microbiome impacts immune function, we investigated the influence of intestinal microbiota composition on RVI and determined that segmented filamentous bacteria (SFB), naturally acquired or exogenously administered, protected mice against influenza virus (IAV) infection. Such protection, which also applied to respiratory syncytial virus and SARS-CoV-2, was independent of interferon and adaptive immunity but required basally resident alveolar macrophages (AM). In SFB-negative mice, AM were quickly depleted as RVI progressed. In contrast, AM from SFB-colonized mice were intrinsically altered to resist IAV-induced depletion and inflammatory signaling. Yet, AM from SFB-colonized mice were not quiescent. Rather, they directly disabled IAV via enhanced complement production and phagocytosis. Accordingly, transfer of SFB-transformed AM into SFB-free hosts recapitulated SFB-mediated protection against IAV. These findings uncover complex interactions that mechanistically link the intestinal microbiota with AM functionality and RVI severity. One sentence summary: Intestinal segmented filamentous bacteria reprogram alveolar macrophages promoting nonphlogistic defense against respiratory viruses.
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Inflammatory bowel disease (IBD) is a multifactorial, chronic disease that affects approximately 1.5 million people in the United States [1]. It presents with inflammation of the intestine with unknown etiology and its two main forms are Crohn's disease (CD) and ulcerative colitis (UC). Several important factors are implicated in the pathogenesis of IBD, one being dysregulation of the immune system resulting in the accumulation and stimulation of innate and adaptive immune cells and subsequent release of soluble factors, including pro-inflammatory cytokines. One of these cytokines is a member of the IL-36 cytokine family, IL-36γ, which is overexpressed in human IBD and experimental mouse models of colitis. In this study, we explored the role of IL-36γ in promoting CD4 + T cell activation and cytokine secretion. We found that IL-36γ stimulation of naïve CD4 + T cells significantly induced IFNγ expression in vitro and was associated with augmented intestinal inflammation in vivo using naive CD4 + cell transfer model of colitis. Using IFNγ-/- CD4 + cells, we observed a dramatic decrease in the ability of TNFα production and delayed colitis. This data not only suggests that IL-36γ is a master regulator of a pro-inflammatory cytokine network involving IFNγ and TNFα, but also highlights the importance of targeting IL-36γ and IFNγ as therapeutic approaches. Our studies have broad implications in relation to targeting specific cytokines in human IBD.
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Interleukin 36 (IL-36) constitutes a group of cytokines that belong to the IL-1 superfamily. Emerging evidence has suggested a role of IL-36 in the pathogenesis of many inflammatory disorders. Intriguingly, in the gastrointestinal tract, IL-36 has a rather complex function. IL-36 receptor ligands are overexpressed in both animal colitis models and human IBD patients and may play both pathogenic and protective roles, depending on the context. IL-36 cytokines comprise three receptor agonists: IL-36α, IL-36ß and IL-36γ, and two receptor antagonists: IL-36Ra and IL-38. All IL-36 receptor agonists bind to the IL-36R complex and exert pleiotropic effects during inflammatory settings. Here, we first briefly review the processing and secretion of IL-36 cytokines. We then focus on the current understanding of the immunology effects of IL-36 in gut immunity. In addition, we also discuss the ongoing trials that aim to blockage IL-36R signalling for treating chronic intestinal inflammation and present some unexplored questions regarding IL-36 research.
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Colitis/inmunología , Inflamación/inmunología , Enfermedades Inflamatorias del Intestino/inmunología , Interleucina-1/metabolismo , Mucosa Intestinal/inmunología , Animales , Modelos Animales de Enfermedad , Humanos , Interleucinas/metabolismo , Terapia Molecular Dirigida , Receptores de Interleucina-1/metabolismo , Transducción de SeñalRESUMEN
The physiological role of T cell anergy induction as a key mechanism supporting self-tolerance remains undefined, and natural antigens that induce anergy are largely unknown. In this report, we used TCR sequencing to show that the recruitment of CD4+CD44+Foxp3-CD73+FR4+ anergic (Tan) cells expands the CD4+Foxp3+ (Tregs) repertoire. Next, we report that blockade in peripherally-induced Tregs (pTregs) formation due to mutation in CNS1 region of Foxp3 or chronic exposure to a selecting self-peptide result in an accumulation of Tan cells. Finally, we show that microbial antigens from Akkermansia muciniphila commensal bacteria can induce anergy and drive conversion of naive CD4+CD44-Foxp3- T (Tn) cells to the Treg lineage. Overall, data presented here suggest that Tan induction helps the Treg repertoire to become optimally balanced to provide tolerance toward ubiquitous and microbiome-derived epitopes, improving host ability to avert systemic autoimmunity and intestinal inflammation.
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Linfocitos T CD4-Positivos/inmunología , Microbiota/inmunología , Linfocitos T Reguladores/inmunología , Animales , Antígenos Bacterianos/inmunología , Autoantígenos/inmunología , Diferenciación Celular , Células Cultivadas , Anergia Clonal , Epítopos de Linfocito T/inmunología , Factores de Transcripción Forkhead/metabolismo , Tolerancia Inmunológica , Activación de Linfocitos , Ratones , Ratones TransgénicosRESUMEN
Enteropathogenic bacterial infections are a global health issue associated with high mortality, particularly in developing countries. Efficient host protection against enteropathogenic bacterial infection is characterized by coordinated responses between immune and nonimmune cells. In response to infection in mice, innate immune cells are activated to produce interleukin (IL)-23 and IL-22, which promote antimicrobial peptide (AMP) production and bacterial clearance. IL-36 cytokines are proinflammatory IL-1 superfamily members, yet their role in enteropathogenic bacterial infection remains poorly defined. Using the enteric mouse pathogen, C.rodentium, we demonstrate that signaling via IL-36 receptor (IL-36R) orchestrates a crucial innate-adaptive immune link to control bacterial infection. IL-36R-deficient mice (Il1rl2-/- ) exhibited significant impairment in expression of IL-22 and AMPs, increased intestinal damage, and failed to contain C. rodentium compared to controls. These defects were associated with failure to induce IL-23 and IL-6, two key IL-22 inducers in the early and late phases of infection, respectively. Treatment of Il1rl2-/- mice with IL-23 during the early phase of C. rodentium infection rescued IL-22 production from group 3 innate lymphoid cells (ILCs), whereas IL-6 administration during the late phase rescued IL-22-mediated production from CD4+ T cell, and both treatments protected Il1rl2-/- mice from uncontained infection. Furthermore, IL-36R-mediated IL-22 production by CD4+ T cells was dependent upon NFκB-p65 and IL-6 expression in dendritic cells (DCs), as well as aryl hydrocarbon receptor (AhR) expression by CD4+ T cells. Collectively, these data demonstrate that the IL-36 signaling pathway integrates innate and adaptive immunity leading to host defense against enteropathogenic bacterial infection.
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Inmunidad Adaptativa , Citrobacter rodentium/inmunología , Infecciones por Enterobacteriaceae/inmunología , Inmunidad Innata , Receptores de Interleucina-1/metabolismo , Animales , Citrobacter rodentium/patogenicidad , Modelos Animales de Enfermedad , Infecciones por Enterobacteriaceae/microbiología , Interleucina-1/metabolismo , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Ratones , Ratones Noqueados , Receptores de Interleucina-1/genética , Transducción de Señal/genética , Transducción de Señal/inmunologíaRESUMEN
Bone morphogenic proteins (BMPs) are members of the transforming growth factor ß (TGF-ß) cytokine family promoting differentiation, homeostasis, and self-renewal of multiple tissues. We show that signaling through the bone morphogenic protein receptor 1α (BMPR1α) sustains expression of FOXP3 in Treg cells in peripheral lymphoid tissues. BMPR1α signaling promotes molecular circuits supporting acquisition and preservation of Treg cell phenotype and inhibiting differentiation of pro-inflammatory effector Th1/Th17 CD4+ T cell. Mechanistically, increased expression of KDM6B (JMJD3) histone demethylase, an antagonist of the polycomb repressive complex 2, underlies lineage-specific changes of T cell phenotypes associated with abrogation of BMPR1α signaling. These results reveal that BMPs are immunoregulatory cytokines mediating maturation and stability of peripheral FOXP3+ regulatory T cells (Treg cells) and controlling generation of iTreg cells. Thus, we establish that BMPs, a large cytokine family, are an essential link between stromal tissues and the adaptive immune system involved in sustaining tissue homeostasis by promoting immunological tolerance.
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Proteínas Morfogenéticas Óseas/inmunología , Citocinas/metabolismo , Factores de Transcripción Forkhead/inmunología , Linfocitos T Reguladores/inmunología , Animales , Humanos , RatonesRESUMEN
The gut microbiome is the largest source of intrinsic non-self-antigens that are continuously sensed by the immune system but typically do not elicit lymphocyte responses. CD4+ T cells are critical to sustain uninterrupted tolerance to microbial antigens and to prevent intestinal inflammation. However, clinical interventions targeting commensal bacteria-specific CD4+ T cells are rare, because only a very limited number of commensal-derived epitopes have been identified. Here, we used a new approach to study epitopes and identify T cell receptors expressed by CD4+Foxp3+ (Treg) cells specific for commensal-derived antigens. Using this approach, we found that antigens from Akkermansia muciniphila reprogram naïve CD4+ T cells to the Treg lineage, expand preexisting microbe specific Tregs, and limit wasting disease in the CD4+ T cell transfer model of colitis. These data suggest that the administration of specific commensal epitopes may help to widen the repertoire of specific Tregs that control intestinal inflammation.
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Thymic central tolerance eliminates most immature T cells with autoreactive T cell receptors (TCR) that recognize self MHC/peptide complexes. Regardless, an unknown number of autoreactive CD4+Foxp3- T cells escape negative selection and in the periphery require continuous suppression by CD4+Foxp3+ regulatory cells (Tregs). Here, we compare immune repertoires of Treg-deficient and Treg-sufficient mice to find Tregs continuously constraining one-third of mature CD4+Foxp3- cells from converting to pathogenic effectors in healthy mice. These dormant pathogenic clones frequently express TCRs activatable by ubiquitous autoantigens presented by class II MHCs on conventional dendritic cells, including self-peptides that select them in the thymus. Our data thus suggest that identification of most potentially autoreactive CD4+ T cells in the peripheral repertoire is critical to harness or redirect these cells for therapeutic advantage.
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Autoinmunidad/inmunología , Linfocitos T CD4-Positivos/inmunología , Receptores de Antígenos de Linfocitos T/inmunología , Animales , Autoantígenos/inmunología , Tolerancia Central/inmunología , Células Dendríticas/inmunología , Factores de Transcripción Forkhead/genética , Antígenos de Histocompatibilidad Clase II/inmunología , Ratones , Ratones Transgénicos , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Linfocitos T Reguladores/inmunología , TimoRESUMEN
Regulatory T cells (TR) show great promise for treating autoimmune diseases, allergies and preventing transplant rejection; however, their clinical application has been hampered by the lack of efficient ex vivo or in vivo expansion strategies. Here we report screening data on 130,000 low molecular weight (LMW) compounds for their TR promoting potential using a self-developed high-throughput cell-based assay. One of the lead compounds, an isoxazolecarboxamide designated as TRP38, efficiently converts naïve CD4+ T cells to TR cells in vitro and protects mice from autoimmune colitis in vivo. In addition, TRP38 can synergize with other compounds and/or cytokines such as rapamycin and TGFß for TR conversion, probably via directly inhibiting P70s6 phosphorylation without affecting mTOR expression, underscoring the importance of complementary and coordinated activity of multiple signaling pathways for the increased level of stable TR cell production.
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Enfermedades Autoinmunes/prevención & control , Colitis/prevención & control , Ensayos Analíticos de Alto Rendimiento/métodos , Linfocitos T Reguladores/efectos de los fármacos , Animales , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Factores de Transcripción Forkhead/análisis , Isoxazoles/farmacología , Ratones , Ratones Endogámicos C57BL , Proteínas Quinasas S6 Ribosómicas 70-kDa/metabolismo , Linfocitos T Reguladores/inmunología , Factor de Crecimiento Transformador beta/fisiologíaRESUMEN
The cytokines of the transforming growth factor-ß (TGF-ß) family promote the growth and differentiation of multiple tissues, but the role of only the founding member, TGF-ß, in regulating the immune responses has been extensively studied. TGF-ß is critical to prevent the spontaneous activation of self-reactive T cells and sustain immune homeostasis. In contrast, in the presence of proinflammatory cytokines, TGF-ß promotes the differentiation of effector T helper 17 (TH17) cells. Abrogating TGF-ß receptor signaling prevents the development of interleukin-17 (IL-17)-secreting cells and protects mice from TH17 cell-mediated autoimmunity. We found that the receptor of another member of TGF-ß family, bone morphogenetic protein receptor 1α (BMPR1α), regulates T helper cell activation. We found that the differentiation of TH17 cells from naive CD4+ T cells was inhibited in the presence of BMPs. Abrogation of BMPR1α signaling during CD4+ T cell activation induced a developmental program that led to the generation of inflammatory effector cells expressing large amounts of IL-17, IFN-γ, and TNF family cytokines and transcription factors defining the TH17 cell lineage. We found that TGF-ß and BMPs cooperated to establish effector cell functions and the cytokine profile of activated CD4+ T cells. Together, our data provide insight into the immunoregulatory function of BMPs.
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Receptores de Proteínas Morfogenéticas Óseas de Tipo 1/inmunología , Transducción de Señal/inmunología , Células Th17/inmunología , Factor de Crecimiento Transformador beta/inmunología , Animales , Receptores de Proteínas Morfogenéticas Óseas de Tipo 1/genética , Receptores de Proteínas Morfogenéticas Óseas de Tipo 1/metabolismo , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Femenino , Perfilación de la Expresión Génica/métodos , Regulación de la Expresión Génica/inmunología , Activación de Linfocitos/genética , Activación de Linfocitos/inmunología , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Transducción de Señal/genética , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Células Th17/metabolismo , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
In the gut, various subsets of intraepithelial T cells (IELs) respond to self or non-self-antigens derived from the body, diet, commensal and pathogenic microbiota. Dominant subset of IELs in the small intestine are TCRαßCD8αα+ cells, which are derived from immature thymocytes that express self-reactive TCRs. Although most of TCRαßCD8αα+ IELs are thymus-derived, their repertoire adapts to microbial flora. Here, using high throughput TCR sequencing we examined how clonal diversity of TCRαßCD8αα+ IELs changes upon exposure to commensal-derived antigens. We found that fraction of CD8αα+ IELs and CD4+ T cells express identical αßTCRs and this overlap raised parallel to a surge in the diversity of microbial flora. We also found that an opportunistic pathogen (Staphylococcus aureus) isolated from mouse small intestine specifically activated CD8αα+ IELs and CD4+ derived T cell hybridomas suggesting that some of TCRαßCD8αα+ clones with microbial specificities have extrathymic origin. We also report that CD8ααCD4+ IELs and Foxp3CD4+ T cells from the small intestine shared many αßTCRs, regardless whether the later subset was isolated from Foxp3CNS1 sufficient or Foxp3CNS1 deficient mice that lacks peripherally-derived Tregs. Overall, our results imply that repertoire of TCRαßCD8αα+ in small intestine expends in situ in response to changes in microbial flora.
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Antígenos Bacterianos/inmunología , Antígenos CD8/metabolismo , Intestino Delgado/inmunología , Linfocitos Intraepiteliales/inmunología , Receptores de Antígenos de Linfocitos T alfa-beta/metabolismo , Infecciones Estafilocócicas/inmunología , Staphylococcus aureus/inmunología , Animales , Antígenos CD8/genética , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/microbiología , Diferenciación Celular , Femenino , Intestino Delgado/metabolismo , Intestino Delgado/microbiología , Linfocitos Intraepiteliales/metabolismo , Linfocitos Intraepiteliales/microbiología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Infecciones Estafilocócicas/metabolismo , Infecciones Estafilocócicas/microbiología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Subgrupos de Linfocitos T/microbiologíaRESUMEN
Increased availability of homeostatic cytokines is considered a major mechanism by which lymphodepletion enhances the efficacy of adoptive T cell therapy (ACT). IL-7 is one such cytokine capable of augmenting the function of tumor-reactive CD8+ T cells. However, whether host-derived IL-7 plays a role in driving the proper function of CD4+ T cells in an ACT setting remains unclear. Here we report that lymphodepleting chemotherapy by cyclophosphamide (CTX) does not lead to increased availability of the endogenous IL-7 in mice. Despite of a paucity of IL-7 in the immune milieu, CTX preconditioning allowed adoptively transferred naïve tumor-specific CD4+ T cells to undergo effector differentiation and regain IL-7Rα expression, giving rise to IL-7-responsive polyfunctional CD4+ effector cells. Correspondingly, supplementation of exogenous recombinant IL-7 markedly amplified and sustained polyfunctional CD4+ effector cells, resulting in improved therapeutic outcome in a mouse lymphoma model. We further demonstrated that the immune-enhancing effects of IL-7 were also applicable to donor CD4+ T cells pre-activated under Th1 polarizing condition. These findings suggest caution in relying on the endogenous IL-7 to enhance donor T cell expansion and persistence after lymphodepleting chemotherapy, and highlight the usefulness of recombinant IL-7 as an adjuvant for adoptive immunotherapy.
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Adyuvantes Inmunológicos/uso terapéutico , Linfocitos T CD4-Positivos/inmunología , Inmunoterapia Adoptiva/métodos , Interleucina-7/uso terapéutico , Linfoma/terapia , Animales , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/trasplante , Linfoma/inmunología , Ratones Endogámicos BALB C , Proteínas Recombinantes/uso terapéuticoRESUMEN
In recent years the combined use of chemotherapy and immunotherapy, collectively termed chemoimmunotherapy, has emerged as a promising treatment option for patients with cancer. Antibiotics are commonly used to reduce infection-related complications in patients undergoing chemotherapy. Intriguingly, accumulating evidence has implicated gut microbiota as a critical determinant of host antitumor immune responses, raising the question as to whether the use of broad-spectrum antibiotics would invariably diminish tumor response to chemoimmunotherapies. We investigated the impact of antibiotics on the therapeutic outcomes of cyclophosphamide (CTX) chemotherapy and adoptive T-cell therapy (ACT) where CTX was used as the host-conditioning regimen in mice. We show that antibiotic prophylaxis dampened the endogenous T cell responses elicited by CTX, and reduced the efficacy of CTX against B-cell lymphoma. In the ACT setting, antibiotics administration impaired the therapeutic effects of adoptively transferred tumor-specific CD4+ T cells in mice with implanted colorectal tumors. In contrast, long-term antibiotic exposure did not affect the efficacy of ACT using CD19-targeting chimeric antigen receptor (CAR) T cells in mice with systemic B-cell lymphoma, although it correlated with prolonged CAR expression and sustained B-cell aplasia. Our study demonstrates that chemoimmunotherapies may have variable reliance on intestinal microbiota for T cell activation and function, and thus have different sensitivities to antibiotic prophylaxis. These findings may have implications for the judicial use of antibiotics in cancer patients receiving chemoimmunotherapies.
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The alkylating agent melphalan is used in the treatment of hematological malignancies, especially multiple myeloma. In the past, the usefulness of melphalan has been solely attributed to its cytotoxicity on fastgrowing cancerous cells. Although the immunomodulatory effects of melphalan were suggested many years ago, only recently has this aspect of melphalan's activity begun to be elucidated at the molecular level. Emerging evidence indicates that melphalan can foster an immunogenic microenvironment by inducing immunogenic cell death (ICD) as characterized by membrane translocation of endoplasmic reticulum protein calreticulin (CRT) and by release of chromatin-binding protein high-mobility group box 1 (HMGB1). In addition, the lympho-depletive effect of melphalan can induce the release of pro-inflammatory cytokines and growth factors, deplete regulatory T cells, and create space to facilitate the expansion of infused tumor-reactive T cells. These features suggest that melphalan can be used as a preparative chemotherapy for adoptive T-cell therapy. This notion is supported by our recent work demonstrating that the combination of melphalan and adoptive transfer of tumor-reactive CD4+ T cells can mediate potent antitumor effects in animal models. This review summarizes the recent advances in understanding and utilizing the immunomodulatory effects of melphalan.
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Adyuvantes Inmunológicos/uso terapéutico , Antineoplásicos/uso terapéutico , Linfocitos T CD4-Positivos/inmunología , Inmunoterapia Adoptiva , Melfalán/uso terapéutico , Neoplasias/inmunología , Neoplasias/terapia , Animales , HumanosRESUMEN
The functional status of CD4(+) T cells is a critical determinant of antitumor immunity. Polyfunctional CD4(+) T cells possess the ability to concomitantly produce multiple Th1-type cytokines, exhibiting a functional attribute desirable for cancer immunotherapy. However, the mechanisms by which these cells are induced are neither defined nor it is clear if these cells can be used therapeutically to treat cancer. Here, we report that CD4(+) T cells exposed to exogenous IL-7 during antigenic stimulation can acquire a polyfunctional phenotype, characterized by their ability to simultaneously express IFNγ, IL-2, TNFα and granzyme B. This IL-7-driven polyfunctional phenotype was associated with increased histone acetylation in the promoters of the effector genes, indicative of increased chromatin accessibility. Moreover, forced expression of a constitutively active (CA) form of STAT5 recapitulated IL-7 in inducing CD4(+) T-cell polyfunctionality. Conversely, the expression of a dominant negative (DN) form of STAT5 abolished the ability of IL-7 to induce polyfunctional CD4(+) T cells. These in-vitro-generated polyfunctional CD4(+) T cells can traffic to tumor and expand intratumorally in response to immunization. Importantly, adoptive transfer of polyfunctional CD4(+) T cells following lymphodepletive chemotherapy was able to eradicate large established tumors. This beneficial outcome was associated with the occurrence of antigen epitope spreading, activation of the endogenous CD8(+) T cells and persistence of donor CD4(+) T cells exhibiting memory stem cell attributes. These findings indicate that IL-7 signaling can impart polyfunctionality and stemness potential to CD4(+) T cells, revealing a previously unknown property of IL-7 that can be exploited in adoptive T-cell immunotherapy.
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Bone morphogenetic proteins (BMPs) are growth factors belonging to the TGF-ß (transforming growth factor ß) superfamily. BMPs were found to regulate multiple cell processes such as proliferation, survival, differentiation, and apoptosis. They were originally described to play a pivotal role in inducing bone, cartilage, ligament, and tendon formation at both heterotopic and orthotopic sites but were found to play a significant role in embryogenesis and development of multiple tissues and organs. Activities of BMPs are regulated by a number of secreted proteins, which modulate their availability to bind cellular receptors. The functions of individual BMPs are highly redundant due to binding the same receptors and inducing overlapping signal transduction pathways. Recently, BMPs were found to regulate cells of the innate and adaptive immune system. BMPs are involved in thymic development of T cells at the early, double negative, as well as later, double positive, stages of thymopoesis. They specifically modulate thymic development of regulatory T cells (T(reg)). In the periphery, BMPs affect T cell activation, promoting generation of T(reg) cells. We found that mice deficient for one of the receptors activated by BMPs demonstrated slower growth of transplantable melanoma tumors.
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Proteínas Morfogenéticas Óseas/metabolismo , Linfocitos T CD4-Positivos/inmunología , Diferenciación Celular/fisiología , Transducción de Señal/fisiología , Timo/crecimiento & desarrollo , Animales , Proteínas Morfogenéticas Óseas/inmunología , Linfocitos T CD4-Positivos/citología , Regulación de la Expresión Génica/fisiología , Humanos , Timo/citología , Timo/inmunologíaRESUMEN
Acute schistosomiasis is characterized by pro-inflammatory responses against tissue- or organ-trapped parasite eggs along with granuloma formation. Here, we describe studies in Cx3cr1(-/-) mice and demonstrate the role of Cx3cr1 in the pathoetiology of granuloma formation during acute schistosomiasis. Mice deficient in Cx3cr1 were protected from granuloma formation and hepatic injury induced by Schistosoma japonicum eggs, as manifested by reduced body weight loss and attenuated hepatomegaly along with preserved liver function. Notably, S. japonicum infection induced high levels of hepatic Cx3cr1 expression, which was predominantly expressed by infiltrating macrophages. Loss of Cx3cr1 rendered macrophages preferentially towards M2 polarization, which then led to a characteristic switch of the host immune defense from a conventional Th1 to a typical Th2 response during acute schistosomiasis. This immune switch caused by Cx3cr1 deficiency was probably associated with enhanced STAT6/PPAR-γ signaling and increased expression of indoleamine 2,3-dioxygenase (IDO), an enzyme that promotes M2 polarization of macrophages. Taken together, our data provide evidence suggesting that CX3CR1 could be a viable therapeutic target for treatment of acute schistosomiasis.
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Parasitosis Hepáticas/etiología , Macrófagos/inmunología , Receptores de Interleucina-8A/deficiencia , Esquistosomiasis Japónica/inmunología , Esquistosomiasis Japónica/patología , Enfermedad Aguda , Animales , Modelos Animales de Enfermedad , Femenino , Granuloma/etiología , Granuloma/inmunología , Granuloma/patología , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Cirrosis Hepática Experimental/etiología , Cirrosis Hepática Experimental/inmunología , Cirrosis Hepática Experimental/patología , Parasitosis Hepáticas/inmunología , Parasitosis Hepáticas/patología , Macrófagos/clasificación , Macrófagos/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Óvulo/inmunología , PPAR gamma/metabolismo , Receptores de Interleucina-8A/genética , Factor de Transcripción STAT6/metabolismo , Schistosoma japonicum/inmunología , Esquistosomiasis Japónica/complicaciones , Transducción de Señal , Células Th2/inmunología , Células Th2/patologíaRESUMEN
Type 1 diabetes is one of the most extensively studied autoimmune diseases, but the cellular and molecular mechanisms leading to T cell-mediated destruction of insulin-producing ß cells are still not well understood. In this study, we show that regulatory T cells (T(regs)) in NOD mice undergo age-dependent loss of suppressor functions exacerbated by the decreased ability of activated effector T cells to upregulate Foxp3 and generate T(regs) in the peripheral organs. This age-dependent loss is associated with reduced intercellular communication mediated by gap junctions, which is caused by impaired upregulation and decreased expression of connexin 43. Regulatory functions can be corrected, even in T cells isolated from aged, diabetic mice, by a synergistic activity of retinoic acid, TGF-ß, and IL-2, which enhance connexin 43 and Foxp3 expression in T(regs) and restore the ability of conventional CD4(+) T cells to upregulate Foxp3 and generate peripherally derived T(regs). Moreover, we demonstrate that suppression mediated by T(regs) from diabetic mice is enhanced by a novel reagent, which facilitates gap junction aggregation. In summary, our report identifies gap junction-mediated intercellular communication as an important component of the T(reg) suppression mechanism compromised in NOD mice and suggests how T(reg) mediated immune regulation can be improved.
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Comunicación Celular/inmunología , Conexina 43/biosíntesis , Diabetes Mellitus Tipo 1/inmunología , Uniones Comunicantes/metabolismo , Linfocitos T Reguladores/citología , Factores de Edad , Animales , Diferenciación Celular/inmunología , Conexina 43/genética , Diabetes Mellitus Tipo 1/genética , Femenino , Factores de Transcripción Forkhead/biosíntesis , Inmunosupresores/inmunología , Interleucina-2/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Factor de Transcripción STAT5/genética , Factor de Transcripción STAT5/metabolismo , Proteína Smad2/metabolismo , Proteína smad3/metabolismo , Linfocitos T Reguladores/inmunología , Factor de Crecimiento Transformador beta/farmacología , Tretinoina/farmacología , Regulación hacia ArribaRESUMEN
Unlike genetic alterations, epigenetic modifications are reversible and amenable to pharmacological interventions, which make them appealing targets for clinical therapy. However, little is known about epigenetic regulation in experimental autoimmune encephalomyelitis (EAE). Here we demonstrated that methyl-CpG-binding domain protein 2 (MBD2), an epigenetic regulator, controls autoimmunity and EAE through T-bet/Hlx. Tbx21 and Hlx underwent a DNA methylation turnover upon polarizations and a unique methylation pattern was essential for TH17 development. Loss of Mbd2 resulted in a defect for reading the information encoded by this methylation turnover, which disrupted the homeostasis of T-bet/Hlx axis and suppressed TH17 differentiation. DNA demethylation induced similar effect on helper T cell differentiation. Therefore, Mbd2(-/-) mice were completely protected from EAE. Pathogenic splenocytes isolated from wild-type mice challenged with MOG35-55 could adoptively transfer disease to Mbd2(-/-) mice. In addition, Mbd2(-/-) mice reconstituted with unstimulated wild-type splenocytes developed EAE as wild-type mice did. These data would provide novel insights into epigenetic regulation of EAE.