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1.
Immunity ; 56(8): 1862-1875.e9, 2023 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-37478853

RESUMO

Loss of oral tolerance (LOT) to gluten, driven by dendritic cell (DC) priming of gluten-specific T helper 1 (Th1) cell immune responses, is a hallmark of celiac disease (CeD) and can be triggered by enteric viral infections. Whether certain commensals can moderate virus-mediated LOT remains elusive. Here, using a mouse model of virus-mediated LOT, we discovered that the gut-colonizing protist Tritrichomonas (T.) arnold promotes oral tolerance and protects against reovirus- and murine norovirus-mediated LOT, independent of the microbiota. Protection was not attributable to antiviral host responses or T. arnold-mediated innate type 2 immunity. Mechanistically, T. arnold directly restrained the proinflammatory program in dietary antigen-presenting DCs, subsequently limiting Th1 and promoting regulatory T cell responses. Finally, analysis of fecal microbiomes showed that T. arnold-related Parabasalid strains are underrepresented in human CeD patients. Altogether, these findings will motivate further exploration of oral-tolerance-promoting protists in CeD and other immune-mediated food sensitivities.


Assuntos
Antígenos , Imunidade Inata , Animais , Camundongos , Humanos , Dieta , Glutens , Células Dendríticas , Tolerância Imunológica
2.
Cell ; 186(9): 1846-1862.e26, 2023 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-37028428

RESUMO

The use of probiotics by cancer patients is increasing, including among those undergoing immune checkpoint inhibitor (ICI) treatment. Here, we elucidate a critical microbial-host crosstalk between probiotic-released aryl hydrocarbon receptor (AhR) agonist indole-3-aldehyde (I3A) and CD8 T cells within the tumor microenvironment that potently enhances antitumor immunity and facilitates ICI in preclinical melanoma. Our study reveals that probiotic Lactobacillus reuteri (Lr) translocates to, colonizes, and persists within melanoma, where via its released dietary tryptophan catabolite I3A, it locally promotes interferon-γ-producing CD8 T cells, thereby bolstering ICI. Moreover, Lr-secreted I3A was both necessary and sufficient to drive antitumor immunity, and loss of AhR signaling within CD8 T cells abrogated Lr's antitumor effects. Further, a tryptophan-enriched diet potentiated both Lr- and ICI-induced antitumor immunity, dependent on CD8 T cell AhR signaling. Finally, we provide evidence for a potential role of I3A in promoting ICI efficacy and survival in advanced melanoma patients.


Assuntos
Limosilactobacillus reuteri , Melanoma , Microambiente Tumoral , Humanos , Dieta , Inibidores de Checkpoint Imunológico , Limosilactobacillus reuteri/metabolismo , Melanoma/terapia , Triptofano/metabolismo , Linfócitos T CD8-Positivos/imunologia , Receptores de Hidrocarboneto Arílico/agonistas
3.
Cell Host Microbe ; 30(7): 1003-1019.e10, 2022 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-35658976

RESUMO

The triggers that drive interferon-γ (IFNγ)-producing CD8 T cell (Tc1 cell)-mediated autoimmune hepatitis (AIH) remain obscure. Here, we show that lack of hematopoietic Tet methylcytosine dioxygenase 2 (Tet2), an epigenetic regulator associated with autoimmunity, results in the development of microbiota-dependent AIH-like pathology, accompanied by hepatic enrichment of aryl hydrocarbon receptor (AhR) ligand-producing pathobionts and rampant Tc1 cell immunity. We report that AIH-like disease development is dependent on both IFNγ and AhR signaling, as blocking either reverts ongoing AIH-like pathology. Illustrating the critical role of AhR-ligand-producing pathobionts in this condition, hepatic translocation of the AhR ligand indole-3-aldehyde (I3A)-releasing Lactobacillus reuteri is sufficient to trigger AIH-like pathology. Finally, we demonstrate that I3A is required for L. reuteri-induced Tc1 cell differentiation in vitro and AIH-like pathology in vivo, both of which are restrained by Tet2 within CD8 T cells. This AIH-disease model may contribute to the development of therapeutics to alleviate AIH.


Assuntos
Proteínas de Ligação a DNA , Dioxigenases , Hepatite Autoimune , Limosilactobacillus reuteri , Fígado , Microbiota , Animais , Proteínas de Ligação a DNA/genética , Dioxigenases/genética , Disbiose/complicações , Hepatite Autoimune/etiologia , Hepatite Autoimune/patologia , Interferon gama , Ligantes , Fígado/imunologia , Fígado/microbiologia , Camundongos , Microbiota/genética , Microbiota/imunologia , Linfócitos T Citotóxicos
4.
Trends Immunol ; 42(2): 137-150, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33422410

RESUMO

One major determinant of systemic immunity during homeostasis and in certain complex multifactorial diseases (e.g. cancer and autoimmune conditions), is the gut microbiota. These commensals can shape systemic immune responses via translocation of metabolites, microbial cell wall components, and viable microbes. In the last few years, bacterial translocation has revealed itself as playing a key, and potentially causal role in mediating immunomodulatory processes in nongastrointestinal diseases. Moreover, recent observations regarding the presence of complex microbial communities and viable bacteria within gut-distal tissues during homeostasis challenge the current paradigm that healthy mammals are entirely sterile at nonmucosal sites. This review discusses our current understanding of how the gut microbiota orchestrates systemic immunity during noninfectious extraintestinal diseases and homeostasis, focusing on the translocation of viable bacteria to gut-distal sites.


Assuntos
Doenças Autoimunes , Microbioma Gastrointestinal , Animais , Imunidade , Inflamação , Simbiose
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