RESUMEN
Infection with parasitic worms (helminths) alters host immune responses and can inhibit pathogenic inflammation. Helminth infection promotes a strong Th2 and T regulatory response while suppressing Th1 and Th17 function. Th2 responses are largely dependent on transcriptional programs directed by Stat6-signaling. We examined the importance of intact T cell Stat6 signaling on helminth-induced suppression of murine colitis that results from T cell transfer into immune-deficient mice. Colonization with the intestinal nematode Heligmosomoides polygyrus bakeri resolves WT T cell transfer colitis. However, if the transferred T cells lack intact Stat6 then helminth exposure failed to attenuate colitis or suppress MLN T cell IFN-γ or IL17 production. Loss of Stat6 signaling resulted in decreased IL10 and increased IFN-γ co-expression by IL-17+ T cells. We also transferred T cells from mice with constitutive T cell expression of activated Stat6 (Stat6VT). These mice developed a severe eosinophilic colitis that also was not attenuated by helminth infection. These results show that T cell expression of intact but regulated Stat6 signaling is required for helminth infection-associated regulation of pathogenic intestinal inflammation.
Asunto(s)
Colitis/inmunología , Nematospiroides dubius/inmunología , Factor de Transcripción STAT6/inmunología , Transducción de Señal/inmunología , Infecciones por Strongylida/inmunología , Linfocitos T Reguladores/inmunología , Animales , Colitis/parasitología , Interferón gamma/inmunología , Interleucina-10/inmunología , Interleucina-17/inmunología , Mucosa Intestinal/inmunología , Mucosa Intestinal/parasitología , Ratones , Ratones Endogámicos C57BL , Células TH1/inmunología , Células TH1/parasitología , Células Th17/inmunología , Células Th17/parasitología , Células Th2/inmunología , Células Th2/parasitologíaRESUMEN
Production of TGF-ß by T cells is key to various aspects of immune homeostasis, with defects in this process causing or aggravating immune-mediated disorders. The molecular mechanisms that lead to TGF-ß generation by T cells remain largely unknown. To address this issue, we take advantage of the fact that intestinal helminths stimulate Th2 cells besides triggering TGF-ß generation by T lymphocytes and regulate immune-mediated disorders. We show that the Th2 cell-inducing transcription factor STAT6 is necessary and sufficient for the expression of TGF-ß propeptide in T cells. STAT6 is also necessary for several helminth-triggered events in mice, such as TGF-ß-dependent suppression of alloreactive inflammation in graft-versus-host disease. Besides STAT6, helminth-induced secretion of active TGF-ß requires cleavage of propeptide by the endopeptidase furin. Thus, for the immune regulatory pathway necessary for TGF-ß production by T cells, our results support a two-step model, composed of STAT6 and furin.
Asunto(s)
Furina/inmunología , Factor de Transcripción STAT6/inmunología , Linfocitos T/inmunología , Factor de Crecimiento Transformador beta/biosíntesis , Animales , Furina/metabolismo , Enfermedad Injerto contra Huésped/inmunología , Ratones , Factor de Transcripción STAT6/metabolismo , Infecciones por Strongylida/inmunologíaRESUMEN
Helminths stimulate the secretion of Th2 cytokines, like IL-4, and suppress lethal graft-versus-host disease (GVHD) after bone marrow transplantation. This suppression depends on the production of immune-modulatory TGF-ß and is associated with TGF-ß-dependent in vivo expansion of Foxp3+ regulatory T cells (Treg). In vivo expansion of Tregs is under investigation for its potential as a therapy for GVHD. Nonetheless, the mechanism of induced and TGF-ß-dependent in vivo expansion of Tregs, in a Th2 polarized environment after helminth infection, is unknown. In this study, we show that helminth-induced IL-4 production by host cells is critical to the induction and maintenance of TGF-ß secretion, TGF-ß-dependent expansion of Foxp3+ Tregs, and the suppression of GVHD. In mice with GVHD, the expanding donor Tregs express the Th2-driving transcription factor, GATA3, which is required for helminth-induced production of IL-4 and TGF-ß. In contrast, TGF-ß is not necessary for GATA3 expression by Foxp3+ Tregs or by Foxp3- CD4 T cells. Various cell types of innate or adaptive immune compartments produce high quantities of IL-4 after helminth infection. As a result, IL-4-mediated suppression of GVHD does not require invariant NKT cells of the host, a cell type known to produce IL-4 and suppress GVHD in other models. Thus, TGF-ß generation, in a manner dependent on IL-4 secretion by host cells and GATA3 expression, constitutes a critical effector arm of helminthic immune modulation that promotes the in vivo expansion of Tregs and suppresses GVHD.
Asunto(s)
Enfermedad Injerto contra Huésped/inmunología , Interleucina-4/biosíntesis , Infecciones por Strongylida/inmunología , Linfocitos T Reguladores/inmunología , Factor de Crecimiento Transformador beta/biosíntesis , Animales , Trasplante de Médula Ósea , Linfocitos T CD4-Positivos/inmunología , Factor de Transcripción GATA3/inmunología , Factor de Transcripción GATA3/metabolismo , Interleucina-4/inmunología , Activación de Linfocitos/inmunología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Nematospiroides dubius , Factor de Crecimiento Transformador beta/inmunologíaRESUMEN
BACKGROUND: Patients with inflammatory bowel disease have higher incidence of airway hyperresponsiveness compared to the general population. Lung inflammation leading to airway hyperresponsiveness causes illnesses for more than ten percent of the population in USA. AIMS: We investigated the lung response to bacterial endotoxin in colitic mice. METHODS: Rag-1 mice were transplanted with negatively selected splenic T cells. Some mice groups were treated with NSAID to develop colitis. All mice were treated with bacterial endotoxin and necropsied 3 weeks later. RESULTS: Colitic mice developed intensified lung inflammation on day 21 of treatment with bacterial endotoxin. Pulmonary lymphocytes from colitic mice displayed a proinflammatory cytokine profile, expressed high ICAM1 and low FoxP3. CD11c+, CD8+ cells bound and responded to non-systemic antigens from gut-localized microbiota and had higher expression of TLR4. CONCLUSIONS: Colitic mice developed exacerbated lung inflammation in response to bacterial endotoxin compared to non-colitic mice. Proinflammatory cytokines from pulmonary lymphocytes induced high expression of ICAM1 and suppressed FoxP3 on CD4+ cells. CD11c+, CD8+ cells binding and responding to gut-localized antigens as well as high expression of TLR4 indicate innate and adaptive lung response to bacterial endotoxin. Inflammatory cells from colons of colitic mice homed in the lungs as well as the intestine suggesting recirculation of sensitized immunocompetent cells. These data support our hypothesis that colitis intensifies lung inflammation.
Asunto(s)
Colitis/complicaciones , Pulmón/inmunología , Hipersensibilidad Respiratoria/etiología , Animales , Movimiento Celular , Colitis/inmunología , Citocinas/metabolismo , Endotoxinas , Femenino , Factores de Transcripción Forkhead/metabolismo , Helmintos , Molécula 1 de Adhesión Intercelular/metabolismo , Pulmón/patología , Linfocitos/metabolismo , Ratones Endogámicos C57BL , Receptor Toll-Like 4/metabolismoRESUMEN
Donor T lymphocyte transfer with hematopoietic stem cells suppresses residual tumor growth (graft-versus-tumor [GVT]) in cancer patients undergoing bone marrow transplantation (BMT). However, donor T cell reactivity to host organs causes severe and potentially lethal inflammation called graft-versus-host disease (GVHD). High-dose steroids or other immunosuppressive drugs are used to treat GVHD that have limited ability to control the inflammation while incurring long-term toxicity. Novel strategies are needed to modulate GVHD, preserve GVT, and improve the outcome of BMT. Regulatory T cells (Tregs) control alloantigen-sensitized inflammation of GVHD, sustain GVT, and prevent mortality in BMT. Helminths colonizing the alimentary tract dramatically increase the Treg activity, thereby modulating intestinal or systemic inflammatory responses. These observations led us to hypothesize that helminths can regulate GVHD and maintain GVT in mice. Acute GVHD was induced in helminth (Heligmosomoides polygyrus)-infected or uninfected BALB/c recipients of C57BL/6 donor grafts. Helminth infection suppressed donor T cell inflammatory cytokine generation and reduced GVHD-related mortality, but maintained GVT. H. polygyrus colonization promoted the survival of TGF-ß-generating recipient Tregs after a conditioning regimen with total body irradiation and led to a TGF-ß-dependent in vivo expansion/maturation of donor Tregs after BMT. Helminths did not control GVHD when T cells unresponsive to TGF-ß-mediated immune regulation were used as donor T lymphocytes. These results suggest that helminths suppress acute GVHD using Tregs and TGF-ß-dependent pathways in mice. Helminthic regulation of GVHD and GVT through intestinal immune conditioning may improve the outcome of BMT.
Asunto(s)
Enfermedad Injerto contra Huésped/inmunología , Helmintos/inmunología , Intestinos/inmunología , Intestinos/parasitología , Neoplasias/inmunología , Enfermedad Aguda , Traslado Adoptivo , Animales , Trasplante de Médula Ósea , Citocinas/biosíntesis , Modelos Animales de Enfermedad , Enfermedad Injerto contra Huésped/metabolismo , Enfermedad Injerto contra Huésped/mortalidad , Helmintiasis Animal/inmunología , Inmunomodulación , Inmunofenotipificación , Masculino , Ratones , Neoplasias/metabolismo , Neoplasias/mortalidad , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Acondicionamiento Pretrasplante , Trasplante HomólogoRESUMEN
Recipient T cells can aggravate or regulate lethal and devastating graft-versus-host disease (GVHD) after bone marrow transplantation (BMT). In this context, we have shown before that intestinal immune conditioning with helminths is associated with survival of recipient T cells and Th2 pathway-dependent regulation of GVHD. We investigated the mechanism of survival of recipient T cells and their contribution to GVHD pathogenesis in this helminth infection and BMT model after myeloablative preparation with total body irradiation in mice. Our results indicate that the helminth-induced Th2 pathway directly promotes the survival of recipient T cells after total body irradiation. Th2 cells also directly stimulate recipient T cells to produce TGF-ß, which is required to regulate donor T cell-mediated immune attack of GVHD and can thereby contribute to recipient T cell survival after BMT. Moreover, we show that recipient T cells, conditioned to produce Th2 cytokines and TGF-ß after helminth infection, are fundamentally necessary for GVHD regulation. Taken together, reprogrammed or immune-conditioned recipient T cells after helminth infection are crucial elements of Th2- and TGF-ß-dependent regulation of GVHD after BMT, and their survival is dependent on cell-intrinsic Th2 signaling.
Asunto(s)
Trasplante de Médula Ósea , Enfermedad Injerto contra Huésped , Ratones , Animales , Trasplante de Médula Ósea/efectos adversos , Células Th2/metabolismo , Citocinas , Factor de Crecimiento Transformador betaRESUMEN
The present report summarizes the United States Department of Veterans Affairs (VA) field-based meeting titled "Modulating microbiome-immune axis in the deployment-related chronic diseases of Veterans." Our Veteran patient population experiences a high incidence of service-related chronic physical and mental health problems, such as infection, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), various forms of hematological and non-hematological malignancies, neurologic conditions, end-stage organ failure, requiring transplantation, and posttraumatic stress disorder (PTSD). We report the views of a group of scientists who focus on the current state of scientific knowledge elucidating the mechanisms underlying the aforementioned disorders, novel therapeutic targets, and development of new approaches for clinical intervention. In conclusion, we dovetailed on four research areas of interest: 1) microbiome interaction with immune cells after hematopoietic cell and/or solid organ transplantation, graft-versus-host disease (GVHD) and graft rejection, 2) intestinal inflammation and its modification in IBD and cancer, 3) microbiome-neuron-immunity interplay in mental and physical health, and 4) microbiome-micronutrient-immune interactions during homeostasis and infectious diseases. At this VA field-based meeting, we proposed to explore a multi-disciplinary, multi-institutional, collaborative strategy to initiate a roadmap, specifically focusing on host microbiome-immune interactions among those with service-related chronic diseases to potentially identify novel and translatable therapeutic targets.
Asunto(s)
Microbioma Gastrointestinal , Enfermedades Inflamatorias del Intestino , Síndrome del Colon Irritable , Microbiota , Veteranos , Humanos , Síndrome del Colon Irritable/terapiaRESUMEN
Parasites have coevolved with humans. Several of them colonize the human body and establish a symbiotic relationship. Other parasites cause severe and lethal diseases. Prevalence of parasitic infections is decreased in highly industrialized countries, largely due to enforced hygienic practices. In contrast, parasites cause significant morbidity and mortality in parts of the world with barriers to effective public hygiene. Some parasites have emerged as potent pathogens in specific patient populations, such as immune suppressed individuals, regardless of sanitation. This article reviews common parasites encountered in clinical practice and, in the setting of host-parasite symbiosis, discusses their immune regulatory role.
Asunto(s)
Parasitosis Intestinales , Parásitos , Enfermedades Parasitarias , Animales , Humanos , Higiene , Parasitosis Intestinales/diagnóstico , Parasitosis Intestinales/epidemiología , Hígado , Enfermedades Parasitarias/epidemiología , PrevalenciaRESUMEN
Colonization with helminthic parasites induces mucosal regulatory cytokines, like IL-10 or TGF-beta, that are important in suppressing colitis. Helminths induce mucosal T cell IL-10 secretion and regulate lamina propria mononuclear cell (LPMC) Th1 cytokine generation in an IL-10-dependent manner in WT mice. Helminths also stimulate mucosal TGF-beta release. As TGF-beta exerts major regulatory effects on T lymphocytes, we investigated the role of T lymphocyte TGF-beta signaling in helminthic modulation of intestinal immunity. T cell TGF-beta signaling is interrupted in TGF-beta receptor II dominant negative (TGF-betaRII DN) mice by T-cell-specific over-expression of a TGF-betaRII DN. We studied LPMC responses in WT and TGF-betaRII DN mice that were uninfected or colonized with the nematode, Heligmosomoides polygyrus. Our results indicate an essential role of T cell TGF-beta signaling in limiting mucosal Th1 and Th2 responses. Furthermore, we demonstrate that helminthic induction of intestinal T cell IL-10 secretion requires intact T cell TGF-beta-signaling pathway. Helminths fail to curtail robust, dysregulated intestinal Th1 cytokine production and chronic colitis in TGF-betaRII DN mice. Thus, T cell TGF-beta signaling is essential for helminthic stimulation of mucosal IL-10 production, helminthic modulation of intestinal IFN-gamma generation and H. polygyrus-mediated suppression of chronic colitis.
Asunto(s)
Citocinas/metabolismo , Nematospiroides dubius/fisiología , Transducción de Señal/fisiología , Infecciones por Strongylida/metabolismo , Linfocitos T/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Animales , Células Cultivadas , Colitis/inmunología , Colitis/metabolismo , Colitis/parasitología , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Interacciones Huésped-Parásitos , Interferón gamma/metabolismo , Interleucina-10/metabolismo , Parasitosis Intestinales/inmunología , Parasitosis Intestinales/metabolismo , Parasitosis Intestinales/parasitología , Intestino Delgado/citología , Intestino Delgado/metabolismo , Intestino Delgado/parasitología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Receptor Tipo II de Factor de Crecimiento Transformador beta , Receptores de Factores de Crecimiento Transformadores beta/genética , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Transducción de Señal/genética , Infecciones por Strongylida/inmunología , Infecciones por Strongylida/parasitología , Linfocitos T/citología , Factor de Crecimiento Transformador beta/genéticaRESUMEN
Helminth exposure appears to protect hosts from inappropriate inflammatory responses, such as those causing inflammatory bowel disease. A recently identified, strongly proinflammatory limb of the immune response is characterized by T cell IL-17 production. Many autoimmune type inflammatory diseases are associated with IL-17 release. Because helminths protect from these diseases, we examined IL-17 production in helminth-colonized mice. We colonized mice with Heligmosomoides polygyrus, an intestinal helminth, and analyzed IL-17 production by lamina propria mononuclear cells (LPMC) and mesenteric lymph node (MLN) cells. Colonization with H. polygyrus reduces IL-17A mRNA by MLN cells and inhibits IL-17 production by cultured LPMC and MLN cells. Helminth exposure augments IL-4 and IL-10 production. Blocking both IL-4 and IL-10, but not IL-10 alone, restores IL-17 production in vitro. Colonization of colitic IL-10-deficient mice with H. polygyrus suppresses LPMC IL-17 production and improves colitis. Ab-mediated blockade of IL-17 improves colitis in IL-10-deficient mice. Thus, helminth-associated inhibition of IL-17 production is most likely an important mechanism mediating protection from inappropriate intestinal inflammation.
Asunto(s)
Tolerancia Inmunológica , Interleucina-17/antagonistas & inhibidores , Interleucina-17/biosíntesis , Mucosa Intestinal/inmunología , Mucosa Intestinal/parasitología , Nematospiroides dubius/crecimiento & desarrollo , Nematospiroides dubius/inmunología , Animales , Células Cultivadas , Colitis/inmunología , Colitis/metabolismo , Colitis/parasitología , Interleucina-17/metabolismo , Interleucina-4/fisiología , Mucosa Intestinal/metabolismo , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/metabolismo , Ganglios Linfáticos/parasitología , Mesenterio , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Infecciones por Strongylida/inmunología , Infecciones por Strongylida/metabolismo , Infecciones por Strongylida/parasitologíaRESUMEN
Inflammatory bowel disease (IBD) comprises a group of chronic, intestinal inflammatory disorders, including ulcerative colitis and Crohn's disease. IBD is characterized by periods of relapse and remission. Long-term progressive intestinal inflammation can result in severe and devastating complications, such as intestinal strictures and/or fistulae. Immune suppressive medications with potent side effects are often used to control inflammation and limit disease activity. Laboratory tests guide various decisions in clinical management of IBD. We discuss tests used to diagnose IBD, assess for relapse or remission, monitor the effectiveness of therapeutic regimen, screen for the maintenance of health, and diagnose or prevent complications.
Asunto(s)
Técnicas de Laboratorio Clínico , Enfermedades Inflamatorias del Intestino/diagnóstico , Adolescente , Adulto , Biomarcadores , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/prevención & control , Endoscopía Gastrointestinal , Femenino , Pruebas Genéticas , Humanos , Enfermedades Inflamatorias del Intestino/complicaciones , Enfermedades Inflamatorias del Intestino/diagnóstico por imagen , Enfermedades Inflamatorias del Intestino/patología , Masculino , Monitoreo Fisiológico/métodos , Trastornos Nutricionales/etiología , Trastornos Nutricionales/prevención & control , Radiografía , Adulto JovenRESUMEN
Molecular and immunologic mechanisms underlying inflammation in inflammatory bowel disease (IBD) are largely unknown. Recent studies have helped better characterize genetic and environmental factors associated with colitis. Discoveries of genetic variants have confirmed that IBD is a bacteria and cytokine-driven pathologic immune response. Data have demonstrated that certain T cell subsets are important in executing the inflammatory cascade. Insufficient regulatory cell activity or modulatory cytokine production results in unrestrained inflammation. Biologic agents that block inflammatory cytokines (anti-TNFalpha antibodies) have been used successfully to treat IBD. Recent advances have also identified mucosal regulatory pathways.
Asunto(s)
Sistema Inmunológico/fisiopatología , Enfermedades Inflamatorias del Intestino/inmunología , Animales , Citocinas/inmunología , Modelos Animales de Enfermedad , Predisposición Genética a la Enfermedad , Humanos , Inmunoterapia , Enfermedades Inflamatorias del Intestino/genética , Enfermedades Inflamatorias del Intestino/terapia , Factores de RiesgoRESUMEN
The human intestine contains 10¹4 bacteria, which outnumber the mammalian cells 10-fold. Certain other commensal or infectious agents, like helminthic parasites, become members of this microbial ecosystem, especially in populations living under less hygienic conditions. Intestinal microbes, also called the microbiome or microbiota, shape the host immune reactivity to self and nonself throughout life. Changes in microbiome composition may impair the maturation of immune regulatory pathways and predispose the host to develop various forms of inflammatory disorders, like Crohn's disease or ulcerative colitis. The microbiome is also critical to successful transplantation of organs or grafts. After allogeneic hematopoietic stem cell transplantation, when the new donor cells, such as T lymphocytes learn to discriminate "the new self from nonself" in the transplant recipient, they need healthy microbiota-derived signals to preserve the immune homeostasis. Restoring microbiota through intestinal delivery of bacterial strains, helminths, fecal microbiota transplantation, or stool substitutes have the potential to improve and correct aberrant immune reactivity in various disorders.
Asunto(s)
Inflamación/terapia , Intestinos/microbiología , Microbiota , Animales , Humanos , Intestinos/inmunologíaRESUMEN
BACKGROUND: Graft-versus-host-disease (GVHD) after liver transplantation (LT) is a deadly complication with very limited data on risk factors, diagnosis and management. We report a case series and a comprehensive review of the literature. METHODS: Data were systematically extracted from reports of GVHD after LT, and from the United Network for Organ Sharing database. Group comparisons were performed. RESULTS: One hundred fifty-six adult patients with GVHD after LT have been reported. Median time to GVHD onset was 28 days. Clinical features were skin rash (92%), pancytopenia (78%), and diarrhea (65%). Six-month mortality with GVHD after LT was 73%. Sepsis was the most common cause of death (60%). Enterobacter bacteremia, invasive aspergillosis, and disseminated Candida infections were frequently reported. Recipient age over 50 years is a risk factor for GVHD after LT. Hepatocellular carcinoma was overrepresented, whereas chronic hepatitis C was underrepresented, in reported United States GVHD cases relative to all United Network for Organ Sharing database LT cases. Mortality rate with treatment of GVHD after LT was 84% with high-dose steroids alone, 75% to 100% with regimens using dose increases of calcineurin inhibitors, and 55% with IL-2 antagonists. Mortality was 25% in small case series using the CD2-blocker alefacept or TNF-α antagonists. CONCLUSIONS: Age older than 50 years and hepatocellular carcinoma appear to be risk factors for GVHD. Hepatitis C may be protective. High-dose steroids and calcineurin inhibitors are ineffective in the treatment of GVHD after LT. CD2-blockers and TNF-α antagonists appear promising. We propose a diagnostic algorithm to assist clinicians in managing adults with GVHD after LT.
Asunto(s)
Carcinoma Hepatocelular/cirugía , Enfermedad Injerto contra Huésped/fisiopatología , Enfermedad Injerto contra Huésped/terapia , Neoplasias Hepáticas/cirugía , Trasplante de Hígado/efectos adversos , Adolescente , Adulto , Anciano , Algoritmos , Bases de Datos Factuales , Complicaciones de la Diabetes/cirugía , Femenino , Humanos , Iowa , Masculino , Persona de Mediana Edad , Factores de Riesgo , Estados Unidos , Universidades , Adulto JovenRESUMEN
Helminths down-regulate inflammation and may prevent development of several autoimmune illnesses, such as inflammatory bowel disease. We determined if exposure to the duodenal helminth Heligmosomoides polygyrus establishes cytokine pathways in the distal intestine that may protect from intestinal inflammation. Mice received 200 H. polygyrus larvae and were studied 2 weeks later. Lamina propria mononuclear cells (LPMC) were isolated from the terminal ileum for analysis and in vitro experiments. Mice with H. polygyrus were resistant to trinitrobenzenesulfonic acid (TNBS)-induced colitis, a Th1 cytokine-dependent inflammation. Heligmosomoides polygyrus did not change the normal microscopic appearance of the terminal ileum and colon and minimally affected LPMC composition. However, colonization altered LPMC cytokine profiles, blocking gamma interferon (IFN-gamma) and interleukin 12 (IL-12) p40 release but promoting IL-4, IL-5, IL-13, and IL-10 secretion. IL-10 blockade in vitro with anti-IL-10 receptor (IL-10R) monoclonal antibody restored LPMC IFN-gamma and IL-12 p40 secretion. IL-10 blockade in vivo worsened TNBS colitis in H. polygyrus-colonized mice. Lamina propria CD4(+) T cells isolated from colonized mice inhibited IFN-gamma production by splenic T cells from worm-free mice. This inhibition did not require cell contact and was dependent on IL-10. Heligmosomoides polygyrus colonization inhibits Th1 and promotes Th2 and regulatory cytokine production in distant intestinal regions without changing histology or LPMC composition. IL-10 is particularly important for limiting the Th1 response. The T-cell origin of these cytokines demonstrates mucosal regulatory T-cell induction.
Asunto(s)
Citocinas/biosíntesis , Intestino Grueso/parasitología , Nematospiroides dubius/inmunología , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Animales , Intestino Grueso/inmunología , Ratones , Ratones Endogámicos C57BL , Infecciones por Strongylida/inmunología , Infecciones por Strongylida/metabolismo , Infecciones por Strongylida/parasitología , Linfocitos T Reguladores/parasitologíaRESUMEN
Helminths are immune modulators that down-regulate colitis in inflammatory bowel disease. In animal models, intestinal bacteria drive colitis and in humans certain alleles of the LPS receptor protein TLR4 increase inflammatory bowel disease susceptibility. To understand helminthic immune modulation in the gut, we studied the influence of intestinal Heligmosomoides polygyrus colonization on LPS-induced lamina propria mononuclear cell (LPMC) cytokine responses in mice. LPS did not stimulate TGFbeta production from LPMC of uninfected mice. LPS strongly induced LPMC from worm-infected animals to secrete TGFbeta, but not TNF-alpha or IL-12. The TGFbeta derived from mucosal T cells. Helminth infection up-regulated TLR4 expression only in lamina propria T cells. LPMC from worm-infected TLR4 mutant animals did not respond to LPS, suggesting that LPS required TLR4 to stimulate TGFbeta secretion. Thus, during helminth infection, LPS challenge induces mucosal T cells to make TGFbeta through a TLR4-dependent process without promoting synthesis of proinflammatory cytokines.
Asunto(s)
Nematospiroides dubius/patogenicidad , Infecciones por Strongylida/inmunología , Linfocitos T/inmunología , Receptor Toll-Like 4/biosíntesis , Factor de Crecimiento Transformador beta/biosíntesis , Animales , Células Cultivadas , Expresión Génica , Inmunidad Mucosa , Técnicas In Vitro , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/inmunología , Lipopolisacáridos/farmacología , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Nematospiroides dubius/inmunología , Infecciones por Strongylida/genética , Linfocitos T/efectos de los fármacos , Receptor Toll-Like 4/genéticaRESUMEN
We investigated whether inhibitory natural killer cell receptor (iNKR) expression contributes to impaired antigen-specific cytotoxicity and interferon-gamma (IFN-gamma) production by CD8 T cells during chronic infection. iNKR immunoglobulin-like transcript-2 (ILT2/CD85j) is expressed on 40-55% of cytomegalovirus (CMV)-, Epstein-Barr virus (EBV)- and human immunodeficiency virus (HIV)-specific CD8 T cells in both healthy and HIV-infected donors. Other iNKRs (CD158a, b1, e1/e2, k, CD94/NKG2A) are expressed on only a small minority of CD8 T cells and are not preferentially expressed on tetramer-staining virus-specific cells. In normal donors, ILT2 is expressed largely on perforin(+) CD27(-) effector cells. However, in HIV-infected donors, only a third of ILT2(+) cells are also perforin(+). In both normal and HIV-infected donors, ILT2(+) cells are prone to spontaneous apoptosis. Therefore, ILT2 is normally expressed during effector cytotoxic T-lymphocyte (CTL) differentiation, but can also be expressed when effector maturation is incomplete, as in HIV infection. The effect of ILT2 on CD8 cell function was assessed by preincubating effector cells with ILT2 antibody. While blocking ILT2 engagement has no appreciable effect on cytotoxicity, it increases antiviral IFN-gamma production by approximately threefold in both normal and HIV-infected donors. Thus, ILT2 expression, increased on antiviral CD8 cells in chronic infection, may interfere with protective CD8 T-cell function by suppressing IFN-gamma production.