RESUMO
Intestinal epithelial cells (IECs) have long been understood to express high levels of major histocompatibility complex class II (MHC class II) molecules but are not considered canonical antigen-presenting cells, and the impact of IEC-MHC class II signaling on gut homeostasis remains enigmatic. As IECs serve as the primary barrier between underlying host immune cells, we reasoned that IEC-intrinsic antigen presentation may play a role in responses toward the microbiota. Mice with an IEC-intrinsic deletion of MHC class II (IECΔMHC class II) are healthy but have fewer microbial-bound IgA, regulatory T cells (Tregs), and immune repertoire selection. This was associated with increased interindividual microbiota variation and altered proportions of two taxa in the ileum where MHC class II on IECs is highest. Intestinal mononuclear phagocytes (MNPs) have similar MHC class II transcription but less surface MHC class II and are capable of acquiring MHC class II from IECs. Thus, epithelial-myeloid interactions mediate development of adaptive responses to microbial antigens within the gastrointestinal tract.
Assuntos
Imunidade Adaptativa , Bactérias/imunologia , Células Epiteliais/imunologia , Microbioma Gastrointestinal , Antígenos de Histocompatibilidade Classe II/imunologia , Íleo/microbiologia , Imunidade nas Mucosas , Sistema Fagocitário Mononuclear/imunologia , Células Mieloides/imunologia , Animais , Antígenos de Bactérias/imunologia , Antígenos de Bactérias/metabolismo , Bactérias/crescimento & desenvolvimento , Bactérias/metabolismo , Linhagem Celular , Colite/imunologia , Colite/metabolismo , Colite/microbiologia , Modelos Animais de Doenças , Células Epiteliais/metabolismo , Células Epiteliais/microbiologia , Feminino , Antígenos de Histocompatibilidade Classe II/metabolismo , Interações Hospedeiro-Patógeno , Íleo/imunologia , Íleo/metabolismo , Imunoglobulina A/imunologia , Imunoglobulina A/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Sistema Fagocitário Mononuclear/metabolismo , Sistema Fagocitário Mononuclear/microbiologia , Células Mieloides/metabolismo , Células Mieloides/microbiologia , Transdução de Sinais , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismoRESUMO
Immunoglobulin A (IgA) is the most abundant antibody at mucosal surfaces and has been the subject of many investigations involving microbiota research in the last decade. Although the classic functions of IgA include neutralization of harmful toxins, more recent investigations have highlighted an important role for IgA in regulating the composition and function of the commensal microbiota. Multiple reviews have comprehensively covered the literature that describes recent, novel mechanisms of action of IgA and development of the IgA response within the intestine. Here we focus on how the interaction between IgA and the microbiota promotes homeostasis with the host to prevent disease.
Assuntos
Microbioma Gastrointestinal/imunologia , Homeostase , Interações entre Hospedeiro e Microrganismos/imunologia , Interações entre Hospedeiro e Microrganismos/fisiologia , Animais , Bactérias/metabolismo , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/microbiologia , Microbioma Gastrointestinal/genética , Microbioma Gastrointestinal/fisiologia , Expressão Gênica , Interações entre Hospedeiro e Microrganismos/genética , Humanos , Imunoglobulina A/imunologia , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/microbiologia , Mucosa Intestinal/imunologia , Intestinos/microbiologia , Doenças Metabólicas/microbiologia , Interações Microbianas/imunologia , Interações Microbianas/fisiologia , Especificidade da Espécie , SimbioseRESUMO
The commensal microbiota influences many aspects of immune system regulation, including T cells, but molecular details of how this occurs are largely unknown. Here we review our findings that the microbiota regulates Erdr1, a secreted apoptotic factor, to control T cell survival. Erdr1 is highly upregulated in CD4+ T cells from germfree mice and antibiotic treated animals, and our study shows that Erdr1 is suppressed by the microbiota via Toll-like receptor signaling and MyD88 dependent pathways. Erdr1 functions in an autocrine fashion and promotes apoptosis through the FAS/FASL pathway. Suppression of Erdr1 leads to survival of autoreactive T cells and exacerbated autoimmune disease in the EAE model, and overexpression of Erdr1 results in lessened disease. This novel T cell apoptotic factor has implications for autoimmunity, cancer biology, and invasive pathogens and thus represents a novel therapeutic target in disease.