RESUMEN
CD8 tissue-resident memory T (TRM) cells provide frontline protection at barrier tissues; however, mechanisms regulating TRM cell development are not completely understood. Priming dictates the migration of effector T cells to the tissue, while factors in the tissue induce in situ TRM cell differentiation. Whether priming also regulates in situ TRM cell differentiation uncoupled from migration is unclear. Here, we demonstrate that T cell priming in the mesenteric lymph nodes (MLN) regulates CD103+ TRM cell differentiation in the intestine. In contrast, T cells primed in the spleen were impaired in the ability to differentiate into CD103+ TRM cells after entry into the intestine. MLN priming initiated a CD103+ TRM cell gene signature and licensed rapid CD103+ TRM cell differentiation in response to factors in the intestine. Licensing was regulated by retinoic acid signaling and primarily driven by factors other than CCR9 expression and CCR9-mediated gut homing. Thus, the MLN is specialized to promote intestinal CD103+ CD8 TRM cell development by licensing in situ differentiation.
Asunto(s)
Linfocitos T CD8-positivos , Tretinoina , Linfocitos T CD8-positivos/metabolismo , Intestinos , Diferenciación Celular , Transducción de Señal , Memoria InmunológicaRESUMEN
Although murine γδ T cells are largely considered innate immune cells, they have recently been reported to form long-lived memory populations. Much remains unknown about the biology and specificity of memory γδ T cells. Here, we interrogated intestinal memory Vγ4 Vδ1 T cells generated after foodborne Listeria monocytogenes (Lm) infection to uncover an unanticipated complexity in the specificity of these cells. Deep TCR sequencing revealed that a subset of non-canonical Vδ1 clones are selected by Lm infection, consistent with antigen-specific clonal expansion. Ex vivo stimulations and in vivo heterologous challenge infections with diverse pathogenic bacteria revealed that Lm-elicited memory Vγ4 Vδ1 T cells are broadly reactive. The Vγ4 Vδ1 T cell recall response to Lm, Salmonella enterica serovar Typhimurium (STm) and Citrobacter rodentium was largely mediated by the γδTCR as internalizing the γδTCR prevented T cell expansion. Both broadly-reactive canonical and pathogen-selected non-canonical Vδ1 clones contributed to memory responses to Lm and STm. Interestingly, some non-canonical γδ T cell clones selected by Lm infection also responded after STm infection, suggesting some level of cross-reactivity. These findings underscore the promiscuous nature of memory γδ T cells and suggest that pathogen-elicited memory γδ T cells are potential targets for broad-spectrum anti-infective vaccines.
Asunto(s)
Infecciones Bacterianas/inmunología , Vacunas Bacterianas/inmunología , Citrobacter rodentium/fisiología , Listeria monocytogenes/fisiología , Células T de Memoria/metabolismo , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Salmonella typhi/fisiología , Animales , Antígenos Bacterianos/inmunología , Células Cultivadas , Reacciones Cruzadas , Secuenciación de Nucleótidos de Alto Rendimiento , Inmunidad Heteróloga , Células T de Memoria/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Transgénicos , Receptores de Antígenos de Linfocitos T gamma-delta/genética , Especificidad del Receptor de Antígeno de Linfocitos TRESUMEN
While immune responses have been rigorously examined after intravenous Listeria monocytogenes (Lm) infection, less is understood about its dissemination from the intestines or the induction of adaptive immunity after more physiologic models of foodborne infection. Consequently, this study focused on early events in the intestinal mucosa and draining mesenteric lymph nodes (MLN) using foodborne infection of mice with Lm modified to invade murine intestinal epithelium (InlAMLm). InlAMLm trafficked intracellularly from the intestines to the MLN and were associated with Batf3-independent dendritic cells (DC) in the lymphatics. Consistent with this, InlAMLm initially disseminated from the gut to the MLN normally in Batf3-/- mice. Activated migratory DC accumulated in the MLN by 3 days post-infection and surrounded foci of InlAMLm. At this time Batf3-/- mice displayed reduced InlAMLm burdens, implicating cDC1 in maximal bacterial accumulation in the MLN. Batf3-/- mice also exhibited profound defects in the induction and gut-homing of InlAMLm-specific effector CD8 T cells. Restoration of pathogen burden did not rescue antigen-specific CD8 T cell responses in Batf3-/- mice, indicating a critical role for Batf3 in generating anti-InlAMLm immunity following foodborne infection. Collectively, these data suggest that DC play diverse, dynamic roles in the early events following foodborne InlAMLm infection and in driving the establishment of intestinal Lm-specific effector T cells.
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Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Linfocitos T CD8-positivos/metabolismo , Células Dendríticas/metabolismo , Enfermedades Transmitidas por los Alimentos/metabolismo , Inmunidad Mucosa , Mucosa Intestinal/metabolismo , Intestino Delgado/metabolismo , Listeria monocytogenes/patogenicidad , Listeriosis/metabolismo , Ganglios Linfáticos/metabolismo , Proteínas Represoras/metabolismo , Animales , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/microbiología , Células Cultivadas , Quimiotaxis de Leucocito , Células Dendríticas/inmunología , Células Dendríticas/microbiología , Modelos Animales de Enfermedad , Femenino , Enfermedades Transmitidas por los Alimentos/genética , Enfermedades Transmitidas por los Alimentos/inmunología , Enfermedades Transmitidas por los Alimentos/microbiología , Interacciones Huésped-Patógeno , Mucosa Intestinal/inmunología , Mucosa Intestinal/microbiología , Intestino Delgado/inmunología , Intestino Delgado/microbiología , Listeria monocytogenes/genética , Listeria monocytogenes/inmunología , Listeriosis/genética , Listeriosis/inmunología , Listeriosis/microbiología , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/microbiología , Masculino , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas Represoras/genéticaRESUMEN
Aging negatively impacts immunity, resulting in inefficient responses to vaccinations and infections. Fibroblastic reticular cells (FRCs) are the major stromal cell subset in lymph nodes (LNs) and play an intricate role in the orchestration and control of adaptive immune responses. Although stromal cells have a major impact on immune responses, the impact of aging on LN stromal cells remains unclear. Quantitative analysis of LN stromal cells by flow cytometry revealed that there are no significant differences in the number of stromal cells in young and aged LN at steady state but after influenza infection aged FRCs have delayed expansion as a result of reduced proliferation. Aged LNs also produce reduced levels of homeostatic chemokines, which correlates with reduced homing of naive T cells. Image analysis reveals that young and aged T-cell zone FRCs have similar morphology at steady state and after infection. Furthermore, aged FRCs did not appear to be a contributing factor in the reduced proliferation of young T cells transferred into aged LNs after influenza infection. These results demonstrate that aging alters LN stromal cell response to challenge and these age-related changes may be an underlying contributor to impaired immune responses in the elderly people.
Asunto(s)
Envejecimiento/inmunología , Quimiocinas/inmunología , Enfermedades del Sistema Inmune/genética , Orthomyxoviridae/patogenicidad , Células del Estroma/inmunología , Análisis de Varianza , Animales , Proliferación Celular/fisiología , Células Cultivadas , Quimiocinas/metabolismo , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Fibroblastos/citología , Fibroblastos/fisiología , Citometría de Flujo/métodos , Enfermedades del Sistema Inmune/inmunología , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Linfocitos T/inmunología , Linfocitos T/metabolismoRESUMEN
While CD4 Th1 cells are required for resistance to intramacrophage infections, adoptive transfer of Th1 cells is insufficient to protect against Salmonella infection. Using an epitope-tagged vaccine strain of Salmonella, we found that effective protection correlated with expanded Salmonella-specific memory CD4 T cells in circulation and nonlymphoid tissues. However, naive mice that previously shared a blood supply with vaccinated partners lacked T cell memory with characteristics of tissue residence and did not acquire robust protective immunity. Using a YFP-IFN-γ reporter system, we identified Th1 cells in the liver of immunized mice that displayed markers of tissue residence, including P2X7, ARTC2, LFA-1, and CD101. Adoptive transfer of liver memory cells after ARTC2 blockade increased protection against highly virulent bacteria. Taken together, these data demonstrate that noncirculating memory Th1 cells are a vital component of immunity to Salmonella infection and should be the focus of vaccine strategies.
Asunto(s)
Memoria Inmunológica/inmunología , Hígado/inmunología , Infecciones por Salmonella/inmunología , Salmonella typhimurium/inmunología , Linfocitos T/inmunología , Células TH1/inmunología , Animales , Células Cultivadas , Femenino , Inmunización , Hígado/microbiología , Ratones , Ratones Endogámicos C57BL , Infecciones por Salmonella/microbiología , Infecciones por Salmonella/prevención & control , Linfocitos T/microbiología , Células TH1/microbiologíaRESUMEN
Aging has a profound impact on multiple facets of the immune system, culminating in aberrant functionality. The architectural disorganization of splenic white pulp is a hallmark of the aging spleen, yet the factors underlying these structural changes are unclear. Fibroblastic reticular cells comprise one stromal cell subset in the spleen that is important for maintenance of architectural organization, yet it remains to be determined how aging impacts these cells. In this study, we sought to determine how aging impacts splenic T cell zone reticular cell (TRC) numbers, morphology, and function. Using a mouse model of aging, we found that aged naive spleens have fewer TRCs than young spleens. This reduction in TRC number correlated with reduced CCL19 and CCL21 concentrations in aged spleens, which may contribute to impaired homing of T cells. CCL21 in both young and aged spleens localized with TRCs. Aged TRCs extended marginally into B cell follicles and may contribute to the blending of the T cell zone and B cell follicles in aged spleens. The described age-related changes in TRCs number and function may be an underlying factor contributing to impaired immune system function with age.
RESUMEN
The development of a subunit Salmonella vaccine has been hindered by the absence of detailed information about antigenic targets of protective Salmonella-specific T and B cells. Recent studies have identified SseB as a modestly protective Ag in susceptible C57BL/6 mice, but the mechanism of protective immunity remains undefined. In this article, we report that simply combining Salmonella SseB with flagellin substantially enhances protective immunity, allowing immunized C57BL/6 mice to survive for up to 30 d following challenge with virulent bacteria. Surprisingly, the enhancing effect of flagellin did not require flagellin Ag targeting during secondary responses or recognition of flagellin by TLR5. Although coimmunization with flagellin did not affect SseB-specific Ab responses, it modestly boosted CD4 responses. In addition, protective immunity was effectively transferred in circulation to parabionts of immunized mice, demonstrating that tissue-resident memory is not required for vaccine-induced protection. Finally, protective immunity required host expression of IFN-γR but was independent of induced NO synthase expression. Taken together, these data indicate that Salmonella flagellin has unique adjuvant properties that improve SseB-mediated protective immunity provided by circulating memory.
Asunto(s)
Proteínas Bacterianas/inmunología , Flagelina/inmunología , Memoria Inmunológica , Chaperonas Moleculares/inmunología , Salmonelosis Animal/prevención & control , Vacunas contra la Salmonella/inmunología , Adyuvantes Inmunológicos , Animales , Anticuerpos Antibacterianos/sangre , Linfocitos T CD4-Positivos/inmunología , Femenino , Inmunización , Ratones , Ratones Endogámicos C57BL , Óxido Nítrico Sintasa/genética , Óxido Nítrico Sintasa/metabolismo , Receptores de Interferón/genética , Receptores de Interferón/inmunología , Vacunas contra la Salmonella/administración & dosificación , Salmonella typhimurium/inmunología , Receptor Toll-Like 5/inmunología , Receptor de Interferón gammaRESUMEN
The development and homeostasis of γδ T cells is highly dependent on distinct cytokine networks. Here we examine the role of IL-15 and its unique receptor, IL-15Rα, in the development of IL-17-producing γδ (γδ-17) T cells. Phenotypic analysis has shown that CD44(high) γδ-17 cells express IL-15Rα and the common gamma chain (CD132), yet lack the IL-2/15Rß chain (CD122). Surprisingly, we found an enlarged population of γδ-17 cells in the peripheral and mesenteric lymph nodes of adult IL-15Rα KO mice, but not of IL-15 KO mice. The generation of mixed chimeras from neonatal thymocytes indicated that cell-intrinsic IL-15Rα expression was required to limit IL-17 production by γδ T cells. γδ-17 cells also were increased in the peripheral lymph nodes of transgenic knock-in mice, where the IL-15Rα intracellular signaling domain was replaced with the intracellular portion of the IL-2Rα chain (that lacks signaling capacity). Finally, an analysis of neonatal thymi revealed that the CD44(lo/int) precursors of γδ-17 cells, which also expressed IL-15Rα, were increased in newborn mice deficient in IL-15Rα signaling, but not in IL-15 itself. Thus, these findings demonstrate that signaling through IL-15Rα regulates the development of γδ-17 cells early in ontogeny, with long-term effects on their peripheral homeostasis in the adult.
Asunto(s)
Subunidad alfa del Receptor de Interleucina-15/metabolismo , Interleucina-17/biosíntesis , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Transducción de Señal , Linfocitos T/citología , Linfocitos T/metabolismo , Animales , Animales Recién Nacidos , Antígenos CD/metabolismo , Movimiento Celular , Fluorescencia , Subunidad alfa del Receptor de Interleucina-15/deficiencia , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Timo/citologíaRESUMEN
The process of lymphopoiesis begins in the bone marrow (BM) and requires multiple cellular intermediates. For T cell production, lymphoid progenitors exit the BM and home to the thymus where maturation and selection ensue. These processes are dependent on a number of factors, including chemokines and adhesion molecules. Although the ß2 integrin CD11a plays an important role in the migration of lymphocytes to lymph nodes, the role of CD11a in T cell development is largely undefined. Our studies now show that, in CD11a(-/-) mice, thymic cellularity was decreased and early T cell development was partially impaired. Remarkably, CD11a was critical for generation of common lymphoid progenitors (CLPs) and lymphoid-primed multipotent progenitors. However, in intact CD11a(-/-) mice, peripheral B and T cell subsets were only modestly altered, suggesting that compensatory mechanisms were operating. In contrast, competitive BM-reconstitution assays revealed an essential role for CD11a in the generation of thymocytes and mature T and B cells. This defect was linked to the requirement for CD11a in the development of CLPs. Furthermore, our results identified CLPs, and not lymphoid-primed multipotent progenitors, as the requisite CD11a-dependent precursor for lymphocyte development. Thus, these findings established a key role for CD11a in lymphopoiesis.
Asunto(s)
Linfocitos B/inmunología , Antígeno CD11a/genética , Células Progenitoras Linfoides/inmunología , Linfopoyesis/genética , Linfocitos T/inmunología , Animales , Linfocitos B/citología , Células de la Médula Ósea/inmunología , Linaje de la Célula , Expresión Génica , Células Progenitoras Linfoides/metabolismo , Linfopoyesis/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Linfocitos T/citologíaRESUMEN
The intestinal mucosa promotes T cell responses that might be beneficial for effective mucosal vaccines. However, intestinal resident memory T (Trm) cell formation and function are poorly understood. We found that oral infection with Listeria monocytogenes induced a robust intestinal CD8 T cell response and blocking effector T cell migration showed that intestinal Trm cells were critical for secondary protection. Intestinal effector CD8 T cells were predominately composed of memory precursor effector cells (MPECs) that rapidly upregulated CD103, which was needed for T cell accumulation in the intestinal epithelium. CD103 expression, rapid MPEC formation, and maintenance in intestinal tissues were dependent on T cell intrinsic transforming growth factor ß signals. Moreover, intestinal Trm cells generated after intranasal or intravenous infection were less robust and phenotypically distinct from Trm cells generated after oral infection, demonstrating the critical contribution of infection route for directing the generation of protective intestinal Trm cells.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Mucosa Intestinal/inmunología , Listeria monocytogenes/inmunología , Listeriosis/inmunología , Listeriosis/transmisión , Enfermedades de la Boca/microbiología , Administración Oral , Traslado Adoptivo , Animales , Antígenos CD/biosíntesis , Movimiento Celular/inmunología , Memoria Inmunológica/inmunología , Cadenas alfa de Integrinas/biosíntesis , Mucosa Intestinal/citología , Listeria monocytogenes/genética , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Factor de Crecimiento Transformador beta/inmunologíaRESUMEN
BACKGROUND: The cell type(s) mediating the maternal influence on allergic disease in children remain unclear. We set out to define the relationship between maternal allergy and frequencies of cord blood (CB) basophils, and plasmacytoid dendritic cells (pDCs); to characterize surface-bound IgE and FcεRI expressions on these cells; and to investigate the association between maternal and CB serum IgE levels with surface-bound IgE and FcεRI expressions. METHODS: One hundred and three mother/infant dyads were recruited prenatally, and maternal allergic history was recorded. Maternal blood was collected prior to delivery, and CB was collected after birth. Flow cytometry was used to identify CB basophils and pDCs and to determine surface-bound IgE and FcεRI expressions. RESULTS: Frequencies of CB basophils and pDCs were low and not related to maternal history of allergy. Percentages of CB basophils with surface-bound IgE were significantly higher in infants of allergic mothers compared with infants of non-allergic mothers (median, 59.60% vs. 19.70%, p = 0.01). IgE on CB basophils correlated with CB IgE levels (r = 0.72, p < 0.0001), but not with maternal IgE levels (r = 0.26, p = 0.06). IgE on CB pDCs was low and not significantly associated with maternal or CB IgE levels. Similarly, FcεRI expression by CB basophils and pDCs was not significantly associated with maternal or CB IgE levels. CONCLUSIONS: Frequencies of CB basophils and pDCs are not influenced by maternal allergy. CB basophils and pDCs have surface-bound IgE and express FcεRI; however, only IgE on CB basophils appears influenced by maternal allergy.
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Basófilos/metabolismo , Sangre Fetal/metabolismo , Hipersensibilidad/inmunología , Inmunoglobulina E/metabolismo , Proteínas de la Membrana/metabolismo , Adulto , Basófilos/inmunología , Separación Celular , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Femenino , Sangre Fetal/inmunología , Citometría de Flujo , Humanos , Inmunidad Materno-Adquirida , Recién Nacido , Masculino , Exposición Materna/efectos adversos , Embarazo , Receptores de IgE/metabolismo , Adulto JovenRESUMEN
Peripheral tolerance to developmentally regulated antigens is necessary to sustain tissue homeostasis. We have now devised an inducible and reversible system that allows interrogation of T-cell tolerance induction in endogenous naïve and memory CD8 T cells. Our data show that peripheral CD8 T-cell tolerance can be preserved through two distinct mechanisms, antigen addiction leading to anergy for naïve T cells and ignorance for memory T cells. Induction of antigen in dendritic cells resulted in substantial expansion and maintenance of endogenous antigen-specific CD8 T cells. The self-reactive cells initially exhibited effector activity but eventually became unresponsive. Upon antigen removal, the antigen-specific population waned, resulting in development of a self-specific memory subset that recalled to subsequent challenge. In striking contrast to naïve CD8 T cells, preexisting antigen-specific memory CD8 T cells failed to expand after antigen induction and essentially ignored the antigen despite widespread expression by dendritic cells. The inclusion of inflammatory signals partially overcame memory CD8 T-cell ignorance of self-antigen. Thus, peripheral CD8 T-cell tolerance for naïve CD8 T cells depended on the continuous presence of antigen, whereas memory CD8 T cells were prohibited from autoreactivity in the absence of inflammation.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Tolerancia Inmunológica/inmunología , Memoria Inmunológica/inmunología , Animales , Autoantígenos/inmunología , Antígenos CD8/inmunología , Linfocitos T CD8-positivos/citología , Activación de Linfocitos/inmunología , Tejido Linfoide/citología , Tejido Linfoide/inmunología , Ratones , Ratones TransgénicosRESUMEN
TNF-α has a multifunctional role in autoimmune diseases as reflected in the variable responses of different human diseases to anti-TNF-α therapy. Recent studies have suggested that TNF-α modulates autoimmunity partially via effects on regulatory T cells (Tregs) and that these effects are mediated through the type II TNFR (TNFR2). We have investigated the requirement for TNFR2-expression on murine natural Tregs (nTregs) and induced Tregs (iTregs) in mediating suppression of colitis. Surprisingly, we find that TNFR2-expression is required for both spleen- and thymus-derived nTreg-mediated suppression, but is not required for iTreg-mediated suppression. Abnormal TNFR2(-/-) nTreg function was not associated with an in vivo decrease in accumulation, stability, or expression of markers known to be relevant in Treg function. Because iTregs are generated in the presence of TGF-ß, we investigated whether activation in the presence of TGF-ß could overcome the functional defect in TNFR2(-/-) nTregs. Although preactivation alone did not restore suppressive function of nTregs, preactivation in the presence of TGF-ß did. These results identify potentially critical differences in activation requirements for nTregs versus iTregs. Furthermore, our findings are consistent with reports suggesting that nTregs are activated in sites of inflammation while iTregs are activated in lymph nodes. Finally, by demonstrating that nTregs require TNF-α for optimal function whereas iTregs do not, our results suggest that the enigma of variable responses of different human diseases to anti-TNF-α therapy may relate to whether nTregs or iTregs have the predominant regulatory role in a given disease.
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Receptores Tipo II del Factor de Necrosis Tumoral/inmunología , Transducción de Señal/inmunología , Linfocitos T Reguladores/inmunología , Factor de Necrosis Tumoral alfa/inmunología , Animales , Enfermedades Autoinmunes/inmunología , Colitis/inmunología , Humanos , Inflamación/inmunología , Ganglios Linfáticos/inmunología , Ratones , Ratones NoqueadosRESUMEN
Vertical transmission of viruses in breast milk can expose neonates to infectious pathogens at a time when the capacity of their immune system to control infections is limited. We developed a mouse model to study the outcomes of acquisition of murine cytomegalovirus (MCMV) when neonates are breastfed by mothers with acute or latent infection. Breast milk leukocytes collected from lactating mice were examined for the presence of MCMV IE-1 mRNA by reverse transcription-PCR (RT-PCR) with Southern analysis. As determined by this criterion, breast milk leukocytes from both acute and latent mothers were positive for MCMV. This mimics the outcome seen in humans with latent cytomegalovirus infection, where reactivation of virus occurs specifically in the lactating mammary gland. Interestingly, intraperitoneal injection of breast milk collected from mothers with latent infection was sufficient to transfer MCMV to neonatal mice, demonstrating that breast milk was a source of virus. Furthermore, we found that MCMV was transmitted from infected mothers to breastfed neonates, with MCMV IE-1 mRNA or infectious virus present in multiple organs, including the brain. In fact, 1 day of nursing was sufficient to transmit MCMV from latent mothers to breastfed neonatal mice. Together, these data validate this mouse model of vertical transmission of MCMV from mothers with acute or latent MCMV infection to breastfed neonates. Its relevance to human disease should prove useful in future studies designed to elucidate the immunological and pathological ramifications of neonatal infection acquired via this natural route.
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Infecciones por Citomegalovirus/transmisión , Transmisión Vertical de Enfermedad Infecciosa , Leche Humana/virología , Muromegalovirus/aislamiento & purificación , Animales , Animales Recién Nacidos , Infecciones por Citomegalovirus/virología , Modelos Animales de Enfermedad , Femenino , Leucocitos/virología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BLRESUMEN
BACKGROUND: The mechanism(s) responsible for the reduced risk of allergic disease in breastfed infants are not fully understood. Using an established murine model of asthma, we demonstrated previously that resistance to allergic airway disease transmitted from allergic mothers to breastfed offspring requires maternal B cell-derived factors. OBJECTIVE: The aim of this study was to investigate the role of offspring neonatal Fc receptor for IgG uptake by intestinal epithelial cells (FcRn) in this breast milk transferred protection from allergy. METHODS: Allergic airway disease was induced during pregnancy in C57BL/6 female mice. These allergic mothers foster nursed naive FcRn+/- or FcRn-/- progeny born to FcRn+/- females that were mated to C57BL/6J-FcRn-/- male mice. In offspring deficient in FcRn, we expected reduced levels of systemic allergen-specific IgG1, a consequence of decreased absorption of maternal IgG from the lumen of the neonatal gastrointestinal tract. Using this model, we were able to investigate how breast milk IgG affected offspring responses to allergic sensitization. RESULTS: Levels of maternal antibodies absorbed from the breast milk of allergic foster mothers were determined in weanling FcRn-sufficient or -deficient mice. Maternal transmission of allergen-specific IgG1 to breastfed FcRn-/- offspring was at levels 103-104 lower than observed in FcRn+/- or FcRn+/+ mice. Five weeks after weaning, when offspring were 8 wk old, mice were sensitized and challenged to evaluate their susceptibility to develop allergic airway disease. Protection, indicated by reduced parameters of disease (allergen-specific IgE in serum, eosinophilic inflammation in the airways and lung) were evident in FcRn-sufficient mice nursed as neonates by allergic mothers. In contrast, FcRn-deficient mice breastfed by the same mothers acquired limited, if any, protection from development of allergen-specific IgE and associated pathology. CONCLUSIONS: FcRn expression was a major factor in determining how breastfed offspring of allergic mothers acquired levels of systemic allergen-specific IgG1 sufficient to inhibit allergic sensitization in this model.
RESUMEN
IL-5 is a pleiotropic cytokine that promotes eosinophil differentiation and survival. While naïve bronchial epithelial cells (BEC) produce low levels of IL-5, the role of BEC-derived IL-5 in allergic airway inflammation is unknown. We now show that BEC, isolated from mice with OVA-induced allergic airway disease (AAD), produced elevated levels of IL-5 mRNA and protein as compared to BEC from naïve mice. To determine the contribution of BEC-derived IL-5 to effector responses in the airways, IL-5 deficient bone marrow chimeric mice were generated in which IL-5 expression was restricted to stromal (e.g. BEC) or hematopoietic cells. When subjected to AAD, IL-5 produced by BECs contributed to mucous metaplasia, airway eosinophilia, and OVA-specific IgA levels. Thus, IL-5 production by BEC can impact the microenvironment of the lung, modifying pathologic and protective immune responses in the airways.
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Asma/inmunología , Bronquios/patología , Células Epiteliales/metabolismo , Interleucina-5/biosíntesis , Traslado Adoptivo , Animales , Asma/sangre , Asma/inducido químicamente , Asma/fisiopatología , Hiperreactividad Bronquial , Células Cultivadas , Modelos Animales de Enfermedad , Eosinofilia , Células Epiteliales/inmunología , Células Epiteliales/patología , Femenino , Inmunidad , Inmunoglobulina A/sangre , Interleucina-5/genética , Interleucina-5/inmunología , Metaplasia , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Quimera por TrasplanteRESUMEN
CD4+ CD25+ Foxp3+ Tregs are critical regulators of immune responses and autoimmune diseases. nTregs are thymically derived; iTregs are converted in the periphery from CD4+ CD25- Foxp3- Teffs. Recent studies reported that GALT CD103+ DCs mediated enhanced iTreg conversion via the secretion of RA. However, the factors regulating RA secretion and hence, the induction of iTregs by DCs are not yet clear. Activation of the nuclear hormone receptor PPARgamma has been shown to induce RA expression in human DCs, and thus, we postulated that PPARgamma activation in DCs may be an important regulator of RA secretion and iTreg generation. Using in vitro and in vivo approaches, we now demonstrate that PPARgamma activation enhances iTreg generation through increased RA synthesis from murine splenic DCs. In addition, we demonstrate that inhibition of DC PPARgamma decreases iTreg generation, suggesting a role for endogenous PPARgamma ligands in this process. Overall, our findings suggest that PPARgamma may be important as a factor that stimulates DCs to produce RA and as a potential mechanism by which PPARgamma ligands ameliorate autoimmunity.
Asunto(s)
Células Dendríticas/metabolismo , Tolerancia Inmunológica/inmunología , Factores Inmunológicos/metabolismo , PPAR gamma/metabolismo , Linfocitos T Reguladores/inmunología , Tretinoina/metabolismo , Transporte Activo de Núcleo Celular/inmunología , Animales , Autoinmunidad/inmunología , Comunicación Celular/inmunología , Regulación hacia Abajo/inmunología , Ratones , Ratones Transgénicos , Receptores Citoplasmáticos y Nucleares/metabolismo , Transducción de Señal/inmunologíaRESUMEN
OBJECTIVE: Breastfeeding is associated with a reduced risk of developing asthma in children. Using a murine model we previously demonstrated that mothers with Th1-type immunity to ovalbumin (OVA) transfer antigen-specific protection from OVA-induced allergic airway disease (AAD) to their offspring. The aim of this study was to evaluate the contribution of breastmilk and maternal B cell immunity from allergic mothers in the vertical transmission of protection from AAD. METHODS: This was investigated using an adoptive nursing strategy. Naive offspring were nursed by allergic wild-type or B cell-deficient foster mothers with histories of Th2-type immunity to OVA. Following weaning, offspring were immunized with OVA-Al(OH)(3) and challenged with aerosolized OVA to induce AAD. RESULTS: Offspring nursed by wild-type OVA-immune foster mothers demonstrated lower levels of OVA-specific immunoglobulin E, interleukin-5, and airway eosinophilia than progeny nursed by naive control mothers. In contrast, offspring nursed by B cell-deficient OVA-immune foster mothers had similar parameters of OVA-induced AAD as progeny nursed by naive control mothers. CONCLUSIONS: These data demonstrate the ability of breastmilk from allergic mothers to protect offspring from AAD was dependent on intact maternal B cell immunity. Nursing alone, when done by wild-type mothers with AAD, was sufficient for offspring to acquire the antigen-specific protective factor(s) from breastmilk.
Asunto(s)
Asma/prevención & control , Linfocitos B/inmunología , Inmunidad Materno-Adquirida , Inmunización , Leche Humana/inmunología , Alérgenos/efectos adversos , Animales , Animales Lactantes , Anticuerpos/sangre , Anticuerpos/inmunología , Asma/inmunología , Modelos Animales de Enfermedad , Femenino , Humanos , Tolerancia Inmunológica , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Recién Nacido , Interleucina-5/sangre , Interleucina-5/inmunología , Ratones , Ratones Endogámicos BALB C , Ovalbúmina/efectos adversos , Ovalbúmina/inmunología , Embarazo , Factores de RiesgoRESUMEN
Immune tolerance to self-antigens is a complex process that utilizes multiple mechanisms working in concert to maintain homeostasis and prevent autoimmunity. We developed a system that revealed a population of self-specific CD8 T cells within the endogenous T cell repertoire. Immunization of ovalbumin (OVA)-expressing transgenic mice with recombinant viruses expressing OVA-peptide variants induced self-reactive T cells in vivo that matured into memory T cells able to respond to secondary infection. However, whereas the avidity of memory cells in normal mice increased dramatically with repeated immunizations, avidity maturation was limited for self-specific CD8 T cells. Despite decreased avidity, such memory cells afforded protection against infection, but did not induce overt autoimmunity. Further, up-regulation of self-antigen expression in dendritic cells using an inducible system promoted programmed death-1 expression, but not clonal expansion of preexisting memory cells. Thus, the self-reactive T cell repertoire is controlled by overlapping mechanisms influenced by antigen dose.