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1.
J Immunol ; 212(11): 1680-1692, 2024 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-38607278

RESUMEN

Plasmacytoid dendritic cells (pDCs) are strongly implicated as a major source of IFN-I in systemic lupus erythematosus (SLE), triggered through TLR-mediated recognition of nucleic acids released from dying cells. However, relatively little is known about how TLR signaling and IFN-I production are regulated in pDCs. In this article, we describe a role for integrin αvß3 in regulating TLR responses and IFN-I production by pDCs in mouse models. We show that αv and ß3-knockout pDCs produce more IFN-I and inflammatory cytokines than controls when stimulated through TLR7 and TLR9 in vitro and in vivo. Increased cytokine production was associated with delayed acidification of endosomes containing TLR ligands, reduced LC3 conjugation, and increased TLR signaling. This dysregulated TLR signaling results in activation of B cells and promotes germinal center (GC) B cell and plasma cell expansion. Furthermore, in a mouse model of TLR7-driven lupus-like disease, deletion of αvß3 from pDCs causes accelerated autoantibody production and pathology. We therefore identify a pDC-intrinsic role for αvß3 in regulating TLR signaling and preventing activation of autoreactive B cells. Because αvß3 serves as a receptor for apoptotic cells and cell debris, we hypothesize that this regulatory mechanism provides important contextual cues to pDCs and functions to limit responses to self-derived nucleic acids.


Asunto(s)
Autoinmunidad , Células Dendríticas , Integrina alfaVbeta3 , Lupus Eritematoso Sistémico , Ratones Noqueados , Transducción de Señal , Receptor Toll-Like 7 , Animales , Ratones , Células Dendríticas/inmunología , Integrina alfaVbeta3/inmunología , Integrina alfaVbeta3/metabolismo , Autoinmunidad/inmunología , Receptor Toll-Like 7/inmunología , Receptor Toll-Like 7/metabolismo , Receptor Toll-Like 7/genética , Lupus Eritematoso Sistémico/inmunología , Transducción de Señal/inmunología , Ratones Endogámicos C57BL , Citocinas/metabolismo , Citocinas/inmunología , Receptor Toll-Like 9/inmunología , Receptor Toll-Like 9/metabolismo , Linfocitos B/inmunología , Autoanticuerpos/inmunología , Glicoproteínas de Membrana/inmunología , Glicoproteínas de Membrana/metabolismo , Activación de Linfocitos/inmunología , Modelos Animales de Enfermedad
2.
Sci Immunol ; 9(91): eabq6541, 2024 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-38181093

RESUMEN

Pore-forming toxins (PFTs) are the largest class of bacterial toxins and contribute to virulence by triggering host cell death. Vertebrates also express endogenous pore-forming proteins that induce cell death as part of host defense. To mitigate damage and promote survival, cells mobilize membrane repair mechanisms to neutralize and counteract pores, but how these pathways are activated is poorly understood. Here, we use a transposon-based gene activation screen to discover pathways that counteract the cytotoxicity of the archetypal PFT Staphylococcus aureus α-toxin. We identify the endolysosomal protein LITAF as a mediator of cellular resistance to PFT-induced cell death that is active against both bacterial toxins and the endogenous pore, gasdermin D, a terminal effector of pyroptosis. Activation of the ubiquitin ligase NEDD4 by potassium efflux mobilizes LITAF to recruit the endosomal sorting complexes required for transport (ESCRT) machinery to repair damaged membrane. Cells lacking LITAF, or carrying naturally occurring disease-associated mutations of LITAF, are highly susceptible to pore-induced death. Notably, LITAF-mediated repair occurs at endosomal membranes, resulting in expulsion of damaged membranes as exosomes, rather than through direct excision of pores from the surface plasma membrane. These results identify LITAF as a key effector that links sensing of cellular damage to repair.


Asunto(s)
Toxinas Bacterianas , Piroptosis , Animales , Muerte Celular , Membrana Celular , Endosomas
3.
Science ; 366(6462)2019 10 11.
Artículo en Inglés | MEDLINE | ID: mdl-31601741

RESUMEN

Epithelial resident memory T (eTRM) cells serve as sentinels in barrier tissues to guard against previously encountered pathogens. How eTRM cells are generated has important implications for efforts to elicit their formation through vaccination or prevent it in autoimmune disease. Here, we show that during immune homeostasis, the cytokine transforming growth factor ß (TGF-ß) epigenetically conditions resting naïve CD8+ T cells and prepares them for the formation of eTRM cells in a mouse model of skin vaccination. Naïve T cell conditioning occurs in lymph nodes (LNs), but not in the spleen, through major histocompatibility complex class I-dependent interactions with peripheral tissue-derived migratory dendritic cells (DCs) and depends on DC expression of TGF-ß-activating αV integrins. Thus, the preimmune T cell repertoire is actively conditioned for a specialized memory differentiation fate through signals restricted to LNs.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Células Dendríticas/inmunología , Memoria Inmunológica , Factor de Crecimiento Transformador beta/metabolismo , Animales , Movimiento Celular , Epidermis/inmunología , Integrina alfaV/genética , Integrina alfaV/metabolismo , Ganglios Linfáticos/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Piel/inmunología
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