RESUMO
Induction of commensal-specific immunity contributes to tissue homeostasis, yet the mechanisms underlying induction of commensal-specific B cells remain poorly understood in part due to a lack of tools to identify these cells. Using phage display, we identified segmented filamentous bacteria (SFB) antigens targeted by serum and intestinal antibodies and generated B cell tetramers to track SFB-specific B cells in gut-associated lymphoid tissues. We revealed a compartmentalized response in SFB-specific B cell activation, with a gradient of immunoglobulin A (IgA), IgG1, and IgG2b isotype production along Peyer's patches contrasted by selective production of IgG2b within mesenteric lymph nodes. V(D)J sequencing and monoclonal antibody generation identified somatic hypermutation driven affinity maturation to SFB antigens under homeostatic conditions. Combining phage display and B cell tetramers will enable investigation of the ontogeny and function of commensal-specific B cell responses in tissue immunity, inflammation, and repair.
Assuntos
Linfócitos B , Animais , Linfócitos B/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Nódulos Linfáticos Agregados/imunologia , Ativação Linfocitária/imunologia , Antígenos de Bactérias/imunologia , Hipermutação Somática de Imunoglobulina , Biblioteca de Peptídeos , Linfonodos/imunologia , Técnicas de Visualização da Superfície Celular , Simbiose/imunologia , Imunoglobulina G/imunologia , Imunoglobulina A/imunologiaRESUMO
In sub-Saharan Africa, multidrug-resistant non-typhoidal Salmonella serovars are a common cause of fatal bloodstream infection. Malnutrition is a predisposing factor, but the underlying mechanisms are unknown. Here we show that vitamin A deficiency, one of the most prevalent micronutrient deficits afflicting African children, increases susceptibility to disseminated non-typhoidal Salmonella disease in mice and impairs terminal neutrophil maturation. Immature neutrophils had reduced expression of Slc11a1, a gene that encodes a metal ion transporter generally thought to restrict pathogen growth in macrophages. Adoptive transfer of SLC11A1-proficient neutrophils, but not SLC11A1-deficient neutrophils, reduced systemic Salmonella burden in Slc11a1-/- mice or mice with vitamin A deficiency. Loss of terminal granulopoiesis regulator CCAAT/enhancer-binding protein ϵ (C/EBPϵ) also decreased neutrophil-mediated control of Salmonella, but not that mediated by peritoneal macrophages. Susceptibility to infection increased in Cebpe-/- Slc11a1+/+ mice compared with wild-type controls, in an Slc11a1-expression-dependent manner. These data suggest that SLC11A1 deficiency impairs Salmonella control in part by blunting neutrophil-mediated defence.
Assuntos
Salmonelose Animal , Deficiência de Vitamina A , Criança , Camundongos , Humanos , Animais , Neutrófilos , Salmonella , MacrófagosRESUMO
The presence of memory lymphocytes in nonlymphoid tissues reflects prior immunological experience and can provide nonspecific defense against infection. In this study, we used a mouse cohousing approach to examine the effect of prior immunological experience on Salmonella and Chlamydia infection. As expected, cohousing of "dirty mice" with specific pathogen-free laboratory mice increased the frequency of effector memory T cells in laboratory mice and enhanced protection against systemic Listeria infection. In contrast, the course of systemic infection with Salmonella and mucosal infection with Chlamydia was largely unaffected by cohousing, despite enhanced frequencies of memory T cells. Thus, cohousing of laboratory mice reliably increases the proportion of memory T cells in circulation, but can it have variable effects on pathogen clearance.
Assuntos
Infecções por Chlamydia , Memória Imunológica , Animais , Linfócitos T CD8-Positivos , Infecções por Chlamydia/microbiologia , Células T de Memória , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Anatomical positioning of memory lymphocytes within barrier tissues accelerates secondary immune responses and is thought to be essential for protection at mucosal surfaces. However, it remains unclear whether resident memory in the female reproductive tract (FRT) is required for Chlamydial immunity. Here, we describe efficient generation of tissue-resident memory CD4 T cells and memory lymphocyte clusters within the FRT after vaginal infection with Chlamydia Despite robust establishment of localized memory lymphocytes within the FRT, naïve mice surgically joined to immune mice, or mice with only circulating immunity following intranasal immunization, were fully capable of resisting Chlamydia infection via the vaginal route. Blocking the rapid mobilization of circulating memory CD4 T cells to the FRT inhibited this protective response. These data demonstrate that secondary protection in the FRT can occur in the complete absence of tissue-resident immune cells. The ability to confer robust protection to barrier tissues via circulating immune memory provides an unexpected opportunity for vaccine development against infections of the FRT.
Assuntos
Anticorpos Antibacterianos/biossíntese , Linfócitos T CD4-Positivos/imunologia , Infecções por Chlamydia/prevenção & controle , Chlamydia muridarum/imunologia , Genitália Feminina/imunologia , Imunização/métodos , Administração Intranasal , Administração Intravaginal , Animais , Antígenos de Bactérias/administração & dosagem , Vacinas Bacterianas/administração & dosagem , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/microbiologia , Movimento Celular/efeitos dos fármacos , Movimento Celular/imunologia , Infecções por Chlamydia/imunologia , Infecções por Chlamydia/microbiologia , Chlamydia muridarum/efeitos dos fármacos , Chlamydia muridarum/crescimento & desenvolvimento , Chlamydia muridarum/patogenicidade , Feminino , Genitália Feminina/efeitos dos fármacos , Genitália Feminina/microbiologia , Imunidade nas Mucosas/efeitos dos fármacos , Memória Imunológica/efeitos dos fármacos , Camundongos , Parabiose/métodosRESUMO
Salmonella infection can cause gastroenteritis in healthy individuals or a serious, systemic infection in immunocompromised patients and has a global impact. CD4 Th1 cells represent the main lymphocyte population that participates in bacterial clearance during both primary and secondary infections in mice of the H-2b haplotype. Previous studies have used congenic mice to examine the function of major histocompatibility complex (MHC) molecules in elimination of this pathogen from the host. In this study, we further characterized the ability of H-2b, H-2k, and H-2u molecules to influence adaptive immunity to Salmonella in MHC congenic mice. By depleting different cell populations during infection, we unexpectedly found that CD8 T cells, in addition to CD4 T cells, play a major role in accelerated clearance of bacteria from H-2k congenic hosts. Our data suggest that CD8 T cells accelerate clearance in some MHC congenic mouse strains and could therefore represent an unexpected contributor to the protective efficacy of Salmonella vaccines outside the typical studies in C57BL/6 mice.
Assuntos
Linfócitos T CD8-Positivos/fisiologia , Salmonelose Animal/imunologia , Salmonelose Animal/microbiologia , Salmonella typhimurium/imunologia , Animais , Linfócitos T CD4-Positivos/metabolismo , Infecções por Chlamydia/imunologia , Infecções por Chlamydia/microbiologia , Chlamydia muridarum , Haplótipos , Interferon gama , Complexo Principal de Histocompatibilidade/genética , CamundongosRESUMO
Chlamydia trachomatis is responsible for an increasing number of sexually transmitted infections in the United States and is a common cause of serious pathology in the female reproductive tract (FRT). Given the impact and incidence of these infections, the production of an effective Chlamydia vaccine is a public health priority. Mouse models of Chlamydia infection have been utilized to develop a detailed and mechanistic understanding of protective immunity in the FRT. These studies reveal that MHC class-II restricted Chlamydia-specific CD4 T cells are critical for primary bacterial clearance and provide effective protection against secondary infection in the FRT. Despite the clear importance of IFN- γ produced by CD4 Th1 cells, there are also suggestions of wider functional heterogeneity in the CD4 T cell response to Chlamydia infection. Understanding the role of this diversity in the CD4 T helper cell response in the FRT should allow a more nuanced view of CD4 T cell biology in the context of Chlamydia infection and may be critical for vaccine development. Here, we summarize our current understanding of CD4 T helper subsets in the clearance of Chlamydia and discuss some areas where knowledge needs to be further extended by additional experimentation.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Infecções por Chlamydia/imunologia , Chlamydia trachomatis/imunologia , Animais , Vacinas Bacterianas/imunologia , Humanos , Interferon gama/imunologia , Células Th1/imunologiaRESUMO
Immune mechanisms responsible for pathogen clearance from the female reproductive tract (FRT) are incompletely defined; in particular, the contribution of lymphocyte trafficking to this process is unclear. CCR7-deficient mice have profoundly altered lymphocyte recirculation and display ectopic formation of lymphocyte aggregates within mucosal nonlymphoid tissues, including the FRT. In this study, we investigated how altered lymphocyte distribution in CCR7-deficient mice would affect host responses to Chlamydia muridarum within the reproductive tract. As expected, CCR7-deficient mice exhibited reduced lymphocyte trafficking to lymph nodes and a corresponding increase in T cell populations within the FRT. After intravaginal infection with Chlamydia, CCR7-deficient mice displayed markedly reduced Ag-specific CD4 T cell responses within the local draining iliac lymph nodes, yet robust Th1 and Th17 responses were prominent in the FRT. In addition, Chlamydia-specific Ab responses were dysregulated in CCR7-deficient mice, displaying an unexpected increase in the systemic IgA responses. Importantly, prominent mucosal immune responses in CCR7-deficient mice increased the efficiency of bacteria clearance from the FRT while reducing tissue-associated inflammation and pathology. Thus, increased numbers of lymphocytes within the FRT result in pathogen clearance with reduced immune-mediated pathology.
Assuntos
Infecções por Chlamydia/imunologia , Infecções por Chlamydia/microbiologia , Chlamydia muridarum/imunologia , Receptores CCR7/imunologia , Infecções do Sistema Genital/imunologia , Infecções do Sistema Genital/microbiologia , Animais , Anticorpos Antibacterianos/biossíntese , Anticorpos Antibacterianos/sangue , Linfócitos T CD4-Positivos/imunologia , Movimento Celular , Chlamydia muridarum/isolamento & purificação , Feminino , Imunoglobulina A/sangue , Inflamação/microbiologia , Linfonodos/imunologia , Camundongos , Camundongos Knockout , Receptores CCR7/deficiência , Receptores CCR7/genética , Células Th1/imunologia , Células Th17/imunologiaRESUMO
Antibiotic intervention is an effective treatment strategy for many bacterial infections and liberates bacterial antigens and stimulatory products that can induce an inflammatory response. Despite the opportunity for bacterial killing to enhance the development of adaptive immunity, patients treated successfully with antibiotics can suffer from reinfection. Studies in mouse models of Salmonella and Chlamydia infection also demonstrate that early antibiotic intervention reduces host protective immunity to subsequent infection. This heightened susceptibility to reinfection correlates with poor development of Th1 and antibody responses in antibiotic-treated mice but can be overcome by delayed antibiotic intervention, thus suggesting a requirement for sustained T cell stimulation for protection. Although the contribution of memory T cell subsets is imperfectly understood in both of these infection models, a protective role for noncirculating memory cells is suggested by recent studies. Together, these data propose a model where antibiotic treatment specifically interrupts tissue-resident memory T cell formation. Greater understanding of the mechanistic basis of this phenomenon might suggest therapeutic interventions to restore a protective memory response in antibiotic-treated patients, thus reducing the incidence of reinfection.