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1.
Nat Cancer ; 1(3): 302-314, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32803171

RESUMO

The cytokine IFN-γ produced by tumor-reactive T cells is a key effector molecule with pleiotropic effects during anti-tumor immune responses. While IFN-γ production is targeted at the immunological synapse, its spatiotemporal activity within the tumor remains elusive. Here, we report that while IFN-γ secretion requires local antigen recognition, IFN-γ diffuses extensively to alter the tumor microenvironment in distant areas. Using intravital imaging and a reporter for STAT1 translocation, we provide evidence that T cells mediate sustained IFN-γ signaling in remote tumor cells. Furthermore, tumor phenotypic alterations required several hours of exposure to IFN-γ, a feature that disfavored local IFN-γ activity over diffusion and bystander activity. Finally, single-cell RNA-seq data from melanoma patients also suggested bystander IFN-γ activity in human tumors. Thus, tumor-reactive T cells act collectively to create large cytokine fields that profoundly modify the tumor microenvironment.


Assuntos
Interferon gama , Microambiente Tumoral , Citocinas , Humanos , Linfócitos T
2.
Cell Host Microbe ; 26(6): 795-809.e5, 2019 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-31784259

RESUMO

The host must develop tolerance to commensal microbes and protective responses to infectious pathogens, yet the mechanisms enabling a privileged relationship with commensals remain largely unknown. Skin colonization by commensal Staphylococcus epidermidis facilitates immune tolerance preferentially in neonates via induction of antigen-specific regulatory T cells (Tregs). Here, we demonstrate that this tolerance is not indiscriminately extended to all bacteria encountered in this early window. Rather, neonatal colonization by Staphylococcus aureus minimally enriches for antigen-specific Tregs and does not prevent skin inflammation upon later-life exposure. S. aureus α-toxin contributes to this response by stimulating myeloid cell production of IL-1ß, which limits S. aureus-specific Tregs. Loss of α-toxin or the IL-1 receptor increases Treg enrichment, whereas topical application of IL-1ß or α-toxin diminishes tolerogenic responses to S. epidermidis. Thus, the preferential activation of a key alarmin pathway facilitates early discrimination of microbial "foe" from "friend," thereby preventing tolerance to a common skin pathogen.


Assuntos
Toxinas Bacterianas/imunologia , Receptores de Interleucina-1/metabolismo , Pele/microbiologia , Infecções Estafilocócicas/imunologia , Linfócitos T Reguladores/imunologia , Animais , Animais Recém-Nascidos , Toxinas Bacterianas/metabolismo , Interações entre Hospedeiro e Microrganismos/imunologia , Tolerância Imunológica , Camundongos , Receptores de Interleucina-1/imunologia , Transdução de Sinais/imunologia , Staphylococcus aureus/imunologia , Staphylococcus epidermidis/imunologia , Simbiose/imunologia , Virulência/imunologia
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