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
Cytokine expression during T cell differentiation is a highly regulated process that involves long-range promoter-enhancer and CTCF-CTCF contacts at cytokine loci. Here, we investigated the impact of dynamic chromatin loop formation within the topologically associating domain (TAD) in regulating the expression of interferon gamma (IFN-γ) and interleukin-22 (IL-22); these cytokine loci are closely located in the genome and are associated with complex enhancer landscapes, which are selectively active in type 1 and type 3 lymphocytes. In situ Hi-C analyses revealed inducible TADs that insulated Ifng and Il22 enhancers during Th1 cell differentiation. Targeted deletion of a 17 bp boundary motif of these TADs imbalanced Th1- and Th17-associated immunity, both in vitro and in vivo, upon Toxoplasma gondii infection. In contrast, this boundary element was dispensable for cytokine regulation in natural killer cells. Our findings suggest that precise cytokine regulation relies on lineage- and developmental stage-specific interactions of 3D chromatin architectures and enhancer landscapes.
Assuntos
Fator de Ligação a CCCTC , Diferenciação Celular , Interferon gama , Interleucina 22 , Interleucinas , Células Th1 , Animais , Fator de Ligação a CCCTC/metabolismo , Fator de Ligação a CCCTC/genética , Células Th1/imunologia , Camundongos , Diferenciação Celular/imunologia , Interferon gama/metabolismo , Sítios de Ligação , Interleucinas/metabolismo , Interleucinas/genética , Elementos Facilitadores Genéticos/genética , Camundongos Endogâmicos C57BL , Cromatina/metabolismo , Toxoplasmose/imunologia , Toxoplasmose/parasitologia , Toxoplasmose/genética , Regulação da Expressão Gênica , Toxoplasma/imunologia , Citocinas/metabolismo , Linhagem da Célula , Células Th17/imunologiaRESUMO
Mammalian barrier surfaces are constitutively colonized by numerous microorganisms. We explored how the microbiota was sensed by the immune system and the defining properties of such responses. Here, we show that a skin commensal can induce T cell responses in a manner that is restricted to non-classical MHC class I molecules. These responses are uncoupled from inflammation and highly distinct from pathogen-induced cells. Commensal-specific T cells express a defined gene signature that is characterized by expression of effector genes together with immunoregulatory and tissue-repair signatures. As such, non-classical MHCI-restricted commensal-specific immune responses not only promoted protection to pathogens, but also accelerated skin wound closure. Thus, the microbiota can induce a highly physiological and pleiotropic form of adaptive immunity that couples antimicrobial function with tissue repair. Our work also reveals that non-classical MHC class I molecules, an evolutionarily ancient arm of the immune system, can promote homeostatic immunity to the microbiota.
Assuntos
Imunidade Adaptativa , Bactérias/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Microbiota/imunologia , Pele/imunologia , Linfócitos T/imunologia , Animais , Regulação da Expressão Gênica/imunologia , Antígenos de Histocompatibilidade Classe I/genética , Camundongos , Camundongos TransgênicosRESUMO
Retinol is shuttled to myeloid cells for conversion to retinoic acid, but the receptor facilitating uptake of SAA:retinol complexes on myeloid cells is unknown. In a recent issue of Science, Bang et al. (2021) use genetic and biochemical approaches to reveal this critical receptor to be LRP1 and show that this axis is essential for intestinal innate and adaptive immune responses.
Assuntos
Tretinoína , Vitamina A , Proteínas de Transporte , Tretinoína/metabolismo , Vitamina A/metabolismoRESUMO
Environmental enteric dysfunction (EED) is a gastrointestinal inflammatory disease caused by malnutrition and chronic infection. EED is associated with stunting in children and reduced efficacy of oral vaccines. To study the mechanisms of oral vaccine failure during EED, we developed a microbiota- and diet-dependent mouse EED model. Analysis of E. coli-labile toxin vaccine-specific CD4+ T cells in these mice revealed impaired CD4+ T cell responses in the small intestine and but not the lymph nodes. EED mice exhibited increased frequencies of small intestine-resident RORγT+FOXP3+ regulatory T (Treg) cells. Targeted deletion of RORγT from Treg cells restored small intestinal vaccine-specific CD4 T cell responses and vaccine-mediated protection upon challenge. However, ablation of RORγT+FOXP3+ Treg cells made mice more susceptible to EED-induced stunting. Our findings provide insight into the poor efficacy of oral vaccines in EED and highlight how RORγT+FOXP3+ Treg cells can regulate intestinal immunity while leaving systemic responses intact.
Assuntos
Toxinas Bacterianas/imunologia , Vacinas contra Escherichia coli/imunologia , Gastroenteropatias/imunologia , Intestino Delgado/imunologia , Linfócitos T Reguladores/imunologia , Administração Oral , Animais , Linhagem Celular , Modelos Animais de Doenças , Drosophila , Escherichia coli/imunologia , Feminino , Fatores de Transcrição Forkhead/metabolismo , Gastroenteropatias/microbiologia , Gastroenteropatias/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , VacinaçãoRESUMO
Infections have been proposed as initiating factors for inflammatory disorders; however, identifying associations between defined infectious agents and the initiation of chronic disease has remained elusive. Here, we report that a single acute infection can have dramatic and long-term consequences for tissue-specific immunity. Following clearance of Yersinia pseudotuberculosis, sustained inflammation and associated lymphatic leakage in the mesenteric adipose tissue deviates migratory dendritic cells to the adipose compartment, thereby preventing their accumulation in the mesenteric lymph node. As a consequence, canonical mucosal immune functions, including tolerance and protective immunity, are persistently compromised. Post-resolution of infection, signals derived from the microbiota maintain inflammatory mesentery remodeling and consequently, transient ablation of the microbiota restores mucosal immunity. Our results indicate that persistent disruption of communication between tissues and the immune system following clearance of an acute infection represents an inflection point beyond which tissue homeostasis and immunity is compromised for the long-term. VIDEO ABSTRACT.
Assuntos
Microbioma Gastrointestinal , Doenças do Sistema Imunitário/microbiologia , Doenças do Sistema Imunitário/patologia , Doenças Linfáticas/patologia , Infecções por Yersinia pseudotuberculosis/imunologia , Yersinia pseudotuberculosis/fisiologia , Movimento Celular , Doença Crônica , Células Dendríticas/patologia , Feminino , Humanos , Doenças Linfáticas/microbiologia , Tecido Linfoide/imunologia , Tecido Linfoide/patologia , Masculino , Mesentério/imunologia , Mesentério/patologia , Organismos Livres de Patógenos Específicos , Infecções por Yersinia pseudotuberculosis/patologiaRESUMO
Innate lymphocytes maintain tissue homeostasis at mucosal barriers, with group 2 innate lymphoid cells (ILC2s) producing type 2 cytokines and controlling helminth infection. While the molecular understanding of ILC2 responses has advanced, the complexity of microenvironmental factors impacting ILC2s is becoming increasingly apparent. Herein, we used single-cell analysis to explore the diversity of gene expression among lung lymphocytes during helminth infection. Following infection, we identified a subset of ILC2s that preferentially expressed Il5-encoding interleukin (IL)-5, together with Calca-encoding calcitonin gene-related peptide (CGRP) and its cognate receptor components. CGRP in concert with IL-33 and neuromedin U (NMU) supported IL-5 but constrained IL-13 expression and ILC2 proliferation. Without CGRP signaling, ILC2 responses and worm expulsion were enhanced. Collectively, these data point to CGRP as a context-dependent negative regulatory factor that shapes innate lymphocyte responses to alarmins and neuropeptides during type 2 innate immune responses.
Assuntos
Inflamação/imunologia , Linfócitos/imunologia , Nippostrongylus/fisiologia , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/metabolismo , Infecções por Strongylida/imunologia , Animais , Células Cultivadas , Citocinas/metabolismo , Imunidade Inata , Interleucina-33/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neuropeptídeos/metabolismo , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/genética , Análise de Célula Única , Células Th2/imunologia , Quimeras de TransplanteRESUMO
The somatosensory nervous system surveils external stimuli at barrier tissues, regulating innate immune cells under infection and inflammation. The roles of sensory neurons in controlling the adaptive immune system, and more specifically immunity to the microbiota, however, remain elusive. Here, we identified a mechanism for direct neuroimmune communication between commensal-specific T lymphocytes and somatosensory neurons mediated by the neuropeptide calcitonin gene-related peptide (CGRP) in the skin. Intravital imaging revealed that commensal-specific T cells are in close proximity to cutaneous nerve fibers in vivo. Correspondingly, we observed upregulation of the receptor for the neuropeptide CGRP, RAMP1, in CD8+ T lymphocytes induced by skin commensal colonization. The neuroimmune CGRP-RAMP1 signaling axis functions in commensal-specific T cells to constrain Type 17 responses and moderate the activation status of microbiota-reactive lymphocytes at homeostasis. As such, modulation of neuroimmune CGRP-RAMP1 signaling in commensal-specific T cells shapes the overall activation status of the skin epithelium, thereby impacting the outcome of responses to insults such as wounding. The ability of somatosensory neurons to control adaptive immunity to the microbiota via the CGRP-RAMP1 axis underscores the various layers of regulation and multisystem coordination required for optimal microbiota-reactive T cell functions under steady state and pathology.
Assuntos
Peptídeo Relacionado com Gene de Calcitonina , Neuroimunomodulação , Peptídeo Relacionado com Gene de Calcitonina/genética , Proteína 1 Modificadora da Atividade de Receptores/genética , Receptores de Peptídeo Relacionado com o Gene de Calcitonina , Imunidade AdaptativaRESUMO
The microbiota plays a fundamental role in the induction, education, and function of the host immune system. In return, the host immune system has evolved multiple means by which to maintain its symbiotic relationship with the microbiota. The maintenance of this dialogue allows the induction of protective responses to pathogens and the utilization of regulatory pathways involved in the sustained tolerance to innocuous antigens. The ability of microbes to set the immunological tone of tissues, both locally and systemically, requires tonic sensing of microbes and complex feedback loops between innate and adaptive components of the immune system. Here we review the dominant cellular mediators of these interactions and discuss emerging themes associated with our current understanding of the homeostatic immunological dialogue between the host and its microbiota.
Assuntos
Imunidade Adaptativa/imunologia , Homeostase/imunologia , Sistema Imunitário/imunologia , Imunidade Inata/imunologia , Microbiota/imunologia , Animais , Interações Hospedeiro-Patógeno/imunologia , Humanos , Sistema Imunitário/microbiologia , Tolerância Imunológica/imunologia , Microbiota/fisiologia , Modelos ImunológicosRESUMO
White adipose tissue bridges body organs and plays a fundamental role in host metabolism. To what extent adipose tissue also contributes to immune surveillance and long-term protective defense remains largely unknown. Here, we have shown that at steady state, white adipose tissue contained abundant memory lymphocyte populations. After infection, white adipose tissue accumulated large numbers of pathogen-specific memory T cells, including tissue-resident cells. Memory T cells in white adipose tissue expressed a distinct metabolic profile, and white adipose tissue from previously infected mice was sufficient to protect uninfected mice from lethal pathogen challenge. Induction of recall responses within white adipose tissue was associated with the collapse of lipid metabolism in favor of antimicrobial responses. Our results suggest that white adipose tissue represents a memory T cell reservoir that provides potent and rapid effector memory responses, positioning this compartment as a potential major contributor to immunological memory.
Assuntos
Tecido Adiposo Branco/transplante , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Memória Imunológica , Toxoplasmose/imunologia , Infecções por Yersinia pseudotuberculosis/imunologia , Tecido Adiposo Branco/imunologia , Animais , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Linfócitos T CD4-Positivos/microbiologia , Linfócitos T CD4-Positivos/parasitologia , Linfócitos T CD8-Positivos/microbiologia , Linfócitos T CD8-Positivos/parasitologia , Expressão Gênica , Genes Reporter , Interferon gama/genética , Interferon gama/imunologia , Interleucina-17/genética , Interleucina-17/imunologia , Interleucina-5/genética , Interleucina-5/imunologia , Metabolismo dos Lipídeos , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Análise de Sobrevida , Transplante de Tecidos , Toxoplasma/imunologia , Toxoplasmose/genética , Toxoplasmose/mortalidade , Toxoplasmose/parasitologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia , Yersinia pseudotuberculosis/imunologia , Infecções por Yersinia pseudotuberculosis/genética , Infecções por Yersinia pseudotuberculosis/microbiologia , Infecções por Yersinia pseudotuberculosis/mortalidadeRESUMO
Th17 cells play crucial roles in host-microbe interactions, but can also promote chronic inflammation and tissue pathology. Factors influencing Th17 cell heterogeneity and effector functions in different inflammatory contexts remain unclear. Schnell et al. demonstrate that intestinal Th17 cells form a reservoir from which pathogenic Th17 cells can be elicited during severe tissue inflammation.
Assuntos
Inflamação , Células Th17 , Homeostase , Humanos , Inflamação/patologiaRESUMO
In this Letter, the 'Competing interests' statement should have stated: 'D.R.L. consults for and has equity in Vedanta Biosciences.' The original Letter has not been corrected.
RESUMO
Both microbial and host genetic factors contribute to the pathogenesis of autoimmune diseases. There is accumulating evidence that microbial species that potentiate chronic inflammation, as in inflammatory bowel disease, often also colonize healthy individuals. These microorganisms, including the Helicobacter species, can induce pathogenic T cells and are collectively referred to as pathobionts. However, how such T cells are constrained in healthy individuals is not yet understood. Here we report that host tolerance to a potentially pathogenic bacterium, Helicobacter hepaticus, is mediated by the induction of RORγt+FOXP3+ regulatory T (iTreg) cells that selectively restrain pro-inflammatory T helper 17 (TH17) cells and whose function is dependent on the transcription factor c-MAF. Whereas colonization of wild-type mice by H. hepaticus promoted differentiation of RORγt-expressing microorganism-specific iTreg cells in the large intestine, in disease-susceptible IL-10-deficient mice, there was instead expansion of colitogenic TH17 cells. Inactivation of c-MAF in the Treg cell compartment impaired differentiation and function, including IL-10 production, of bacteria-specific iTreg cells, and resulted in the accumulation of H. hepaticus-specific inflammatory TH17 cells and spontaneous colitis. By contrast, RORγt inactivation in Treg cells had only a minor effect on the bacteria-specific Treg and TH17 cell balance, and did not result in inflammation. Our results suggest that pathobiont-dependent inflammatory bowel disease is driven by microbiota-reactive T cells that have escaped this c-MAF-dependent mechanism of iTreg-TH17 homeostasis.
Assuntos
Colite/imunologia , Colite/microbiologia , Helicobacter hepaticus/imunologia , Tolerância Imunológica , Intestinos/imunologia , Intestinos/microbiologia , Proteínas Proto-Oncogênicas c-maf/metabolismo , Linfócitos T Reguladores/imunologia , Animais , Bioengenharia , Colite/patologia , Feminino , Fatores de Transcrição Forkhead/metabolismo , Helicobacter hepaticus/genética , Helicobacter hepaticus/patogenicidade , Homeostase , Interações Hospedeiro-Patógeno , Interleucina-10/biossíntese , Interleucina-10/deficiência , Interleucina-10/imunologia , Masculino , Camundongos , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/antagonistas & inibidores , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Proteínas Proto-Oncogênicas c-maf/deficiência , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/metabolismo , Células Th17/citologia , Células Th17/imunologiaRESUMO
E-cadherin plays a central role in cell-cell adhesion. The ectodomains of wild-type cadherins form a crystalline-like two-dimensional lattice in cell-cell interfaces mediated by both trans (apposed cell) and cis (same cell) interactions. In addition to these extracellular forces, adhesive strength is further regulated by cytosolic phenomena involving α and ß catenin-mediated interactions between cadherin and the actin cytoskeleton. Cell-cell adhesion can be further strengthened under tension through mechanisms that have not been definitively characterized in molecular detail. Here we quantitatively determine the role of the cadherin ectodomain in mechanosensing. To this end, we devise an E-cadherin-coated emulsion system, in which droplet surface tension is balanced by protein binding strength to give rise to stable areas of adhesion. To reach the honeycomb/cohesive limit, an initial emulsion compression by centrifugation facilitates E-cadherin trans binding, whereas a high protein surface concentration enables the cis-enhanced stabilization of the interface. We observe an abrupt concentration dependence on recruitment into adhesions of constant crystalline density, reminiscent of a first-order phase transition. Removing the lateral cis interaction with a "cis mutant" shifts this transition to higher surface densities leading to denser, yet weaker adhesions. In both proteins, the stabilization of progressively larger areas of deformation is consistent with single-molecule experiments that show a force-dependent lifetime enhancement in the cadherin ectodomain, which may be attributed to the "X-dimer" bond.
Assuntos
Biomimética , Caderinas , Emulsões , Caderinas/metabolismo , Adesão Celular , Ligação ProteicaRESUMO
Under steady-state conditions, the immune system is poised to sense and respond to the microbiota. As such, immunity to the microbiota, including T cell responses, is expected to precede any inflammatory trigger. How this pool of preformed microbiota-specific T cells contributes to tissue pathologies remains unclear. Here, using an experimental model of psoriasis, we show that recall responses to commensal skin fungi can significantly aggravate tissue inflammation. Enhanced pathology caused by fungi preexposure depends on Th17 responses and neutrophil extracellular traps and recapitulates features of the transcriptional landscape of human lesional psoriatic skin. Together, our results propose that recall responses directed to skin fungi can directly promote skin inflammation and that exploration of tissue inflammation should be assessed in the context of recall responses to the microbiota.
Assuntos
Arthrodermataceae/fisiologia , Microbiota , Psoríase/imunologia , Pele/microbiologia , Animais , Arthrodermataceae/classificação , Arthrodermataceae/genética , Arthrodermataceae/isolamento & purificação , Armadilhas Extracelulares/imunologia , Armadilhas Extracelulares/microbiologia , Feminino , Humanos , Imunidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Psoríase/microbiologia , Psoríase/patologia , Pele/imunologia , Pele/patologia , Simbiose , Células Th17/imunologiaRESUMO
NOD2 is an intracellular sensor that contributes to immune defense and inflammation. Here we investigated whether NOD2 mediates its effects through control of microRNAs (miRNAs). miR-29 expression was upregulated in human dendritic cells (DCs) in response to NOD2 signals, and miR-29 regulated the expression of multiple immune mediators. In particular, miR-29 downregulated interleukin-23 (IL-23) by targeting IL-12p40 directly and IL-23p19 indirectly, likely via reduction of ATF2. DSS-induced colitis was worse in miR-29-deficient mice and was associated with elevated IL-23 and T helper 17 signature cytokines in the intestinal mucosa. Crohn's disease (CD) patient DCs expressing NOD2 polymorphisms failed to induce miR-29 upon pattern recognition receptor stimulation and showed enhanced release of IL-12p40 on exposure to adherent invasive E. coli. Therefore, we suggest that loss of miR-29-mediated immunoregulation in CD DCs might contribute to elevated IL-23 in this disease.
Assuntos
Doença de Crohn/imunologia , Células Dendríticas/imunologia , Interleucina-23/metabolismo , MicroRNAs/metabolismo , Proteína Adaptadora de Sinalização NOD2/metabolismo , Fator 2 Ativador da Transcrição/metabolismo , Animais , Células Cultivadas , Células Dendríticas/metabolismo , Escherichia coli/imunologia , Infecções por Escherichia coli/imunologia , Humanos , Inflamação/imunologia , Subunidade p40 da Interleucina-12/metabolismo , Mucosa Intestinal/imunologia , Camundongos , Camundongos Knockout , MicroRNAs/genética , Proteína Adaptadora de Sinalização NOD2/genética , Polimorfismo de Nucleotídeo Único , Células Th17/imunologiaRESUMO
INTRODUCTION: Body dysmorphic disorder (BDD) is severe, chronic, and undertreated. Apps could substantially improve treatment access. OBJECTIVE: We provide an initial test of the usability and efficacy of coach-supported app-based cognitive behavioral therapy (CBT) for BDD. The Perspectives app covers core treatment components: psychoeducation, cognitive restructuring, exposure with response prevention, mindfulness, attention retraining, and relapse prevention. METHODS: A randomized waitlist-controlled trial was conducted. Adults (N = 80) with primary BDD were assigned to 12 weeks of Perspectives or waitlist. Coaches promoted engagement and answered questions via in-app messaging and phone calls. BDD severity was measured at baseline, mid-treatment, and end of treatment by blinded independent evaluators (Yale-Brown Obsessive Compulsive Scale Modified for BDD; BDD-YBOCS). Secondary outcomes included BDD-related insight, depression, quality of life, and functioning. RESULTS: App uptake and satisfaction were high. In intent-to-treat analyses, Perspectives app-based CBT was associated with significantly lower BDD-YBOCS severity at end of treatment (M [SD]: 16.8 [7.5]) compared to the waitlist (26.7 [6.2]; p < 0.001, d = 1.44). App-based CBT was associated with greater improvements across all secondary measures, with medium to large effects. CONCLUSIONS: Perspectives, supported by a bachelor's-level coach, is an efficacious, scalable treatment for adults with BDD.
Assuntos
Transtornos Dismórficos Corporais , Terapia Cognitivo-Comportamental , Aplicativos Móveis , Adulto , Transtornos Dismórficos Corporais/psicologia , Transtornos Dismórficos Corporais/terapia , Humanos , Qualidade de Vida/psicologia , Resultado do TratamentoRESUMO
The cross-talk between the microbiota and the immune system plays a fundamental role in the control of host physiology. However, the tissue-specific factors controlling this dialogue remain poorly understood. Here we demonstrate that T cell responses to commensal colonization are associated with the development of organized cellular clusters within the skin epithelium. These organized lymphocyte clusters are surrounded by keratinocytes expressing a discrete program associated with antigen presentation and antimicrobial defense. Notably, IL-22-mediated keratinocyte-intrinsic MHC class II expression was required for the selective accumulation of commensal-induced IFN-γ, but not IL-17A-producing CD4+ T cells within the skin. Taking these data together, this work uncovers an unexpected role for MHC class II expression by keratinocytes in the control of homeostatic type 1 responses to the microbiota. Our findings have important implications for the understanding of the tissue-specific rules governing the dialogue between a host and its microbiota.
Assuntos
Epiderme/microbiologia , Antígenos de Histocompatibilidade Classe II/biossíntese , Interações entre Hospedeiro e Microrganismos/imunologia , Queratinócitos/imunologia , Microbiota/imunologia , Células Th1/imunologia , Animais , Apresentação de Antígeno , Candida albicans/imunologia , Epiderme/imunologia , Genes MHC da Classe II , Interferon gama/biossíntese , Queratinócitos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Especificidade de Órgãos , Quimera por Radiação , Organismos Livres de Patógenos Específicos , Staphylococcus aureus/imunologia , Staphylococcus epidermidis/imunologia , Simbiose , Células Th1/metabolismoRESUMO
E-cadherins play a critical role in the formation of cell-cell adhesions for several physiological functions, including tissue development, repair, and homeostasis. The formation of clusters of E-cadherins involves extracellular adhesive (trans-) and lateral (cis-) associations between E-cadherin ectodomains and stabilization through intracellular binding to the actomyosin cytoskeleton. This binding provides force to the adhesion and is required for mechanotransduction. However, the exact role of cytoskeletal force on the clustering of E-cadherins is not well understood. To gain insights into this mechanism, we developed a computational model based on Brownian dynamics. In the model, E-cadherins transit between structural and functional states; they are able to bind and unbind other E-cadherins on the same and/or opposite cell(s) through trans- and cis-interactions while also creating dynamic links with the actomyosin cytoskeleton. Our results show that actomyosin force governs the fraction of E-cadherins in clusters and the size and number of clusters. For low forces (below 10 pN), a large number of small E-cadherin clusters form with less than five E-cadherins each. At higher forces, the probability of forming fewer but larger clusters increases. These findings support the idea that force reinforces cell-cell adhesions, which is consistent with differences in cluster size previously observed between apical and lateral junctions of epithelial tissues.