A Wave of Regulatory T Cells into Neonatal Skin Mediates Tolerance to Commensal Microbes

Scharschmidt, Tiffany C.; Vasquez, Kimberly S.; Truong, Hong-An; Gearty, Sofia V; Pauli, Mariela; Nosbaum, Audrey; Gratz, Iris K.; Otto, Michael; Moon, James; Liese, Jan; Abbas, Abul K.; Fischbach, Michael A.; Rosenblum, Michael D.

doi:10.1016/j.immuni.2015.10.016

Cited by 447 publications

(454 citation statements)

References 58 publications

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“…Nevertheless, a previous study showed that extracellular products of S. epidermidis promoted the suppressive activity of human Tregs (47), further indicating that this cell population may be involved in counterinflammatory mechanisms operating during infections with this bacterium. Tregs were recently shown to be crucial for establishing S. epidermidis skin commensalism (48). Taking our results into account, it will also be interesting to ascertain in future studies whether Tregs may contribute to the persistence of biofilm-related S. epidermidis infections (49).…”

Section: Discussionmentioning

confidence: 65%

Poly- N -Acetylglucosamine Production by Staphylococcus epidermidis Cells Increases Their In Vivo Proinflammatory Effect

et al. 2016

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Staphylococcus epidermidis is a commensal bacterium of human skin and mucous membranes (1). The ability to establish biofilms on the surfaces of indwelling medical devices is a major virulence mechanism of this bacterium, which is the most commonly isolated etiological agent of nosocomial infections (2). S. epidermidis biofilm formation involves initial cellular adherence to a surface, followed by intercellular aggregation and accumulation in multilayer cell clusters (1). This process is dependent on adhesive extracellular molecules (3) such as poly-N-acetylglucosamine (PNAG). PNAG is a major factor mediating cell-to-cell adhesion in staphylococci (4, 5), and its production depends on genes encoded within the intercellular adhesion (ica) locus (6). The final stage of the biofilm life cycle comprises cell disassembly and subsequent growth in a planktonic mode, a process contributing to S. epidermidis biofilm pathogenesis by disseminating infection (7).S. epidermidis strains with impaired PNAG production display attenuated virulence in foreign body infection models (8, 9), while the production of this polysaccharide conferred a survival advantage on this bacterium infecting the nematode host Caenorhabditis elegans (10). Moreover, ica mutants display growth attenuation when competing in vivo with the corresponding wild-type (WT) strains (11) and commensal ica-negative strains became invasive when transformed with a plasmid containing the ica locus (12). In the clinical setting, the presence of icaA/D genes was associated with therapeutic failure in device-related infections with coagulase-negative staphylococci (13). Despite the observed association of PNAG production with S. epidermidis virulence, it is not entirely clear how this polysaccharide may affect the host immune response. Previous reports have shown that PNAG stimulates the production of proinflammatory mediators (14, 15) but also that it impairs phagocytosis and phagocyte-mediated bacterial killing (16-18). Additionally, little is known about the effects of this polysaccharide on acquired immunity. Here, by using the PNAG-producing S. epidermidis 9142 strain and a PNAG-negative isogenic M10 mutant, we have addressed in the murine model how this polysaccharide affected the host inflammatory response. The results obtained show that mice infected with a PNAG-producing S. epidermidis strain exhibited a more intense inflammatory response than mice infected with an isogenic PNAG-negative mutant. MATERIALS AND METHODSBacteria and growth conditions. Biofilm-forming S. epidermidis strain 9142 (19) and the isogenic PNAG-negative M10 mutant (5) were used. Absence of growth defects in the M10 strain was confirmed, as the two strains had similar generation times, as determined by growing 9142 and M10 bacteria in tryptic soy broth (TSB; Merck, Darmstadt, Germany).

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Section: Discussionmentioning

confidence: 65%

Poly- N -Acetylglucosamine Production by Staphylococcus epidermidis Cells Increases Their In Vivo Proinflammatory Effect

et al. 2016

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“…Although little is understood about the factors that regulate the acquisition of skin microbes at birth, regulatory T cells, which are highly enriched in the skin tissue, have been proposed to control early dialogue with the microbiota. Indeed, colonization of mouse skin with S. epidermidis early in life (but not later) induces tolerance to the same microbe in adulthood 61 and promotes accumulation of S. epidermidis -specific regulatory T cells in neonatal skin 62 .…”

Section: Host–mutualist Interactionsmentioning

confidence: 99%

Skin microbiota–host interactions

Chen

Fischbach

Belkaid

2018

Nature

539

396

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The skin is a complex and dynamic ecosystem that is inhabited by bacteria, archaea, fungi and viruses. These microbes—collectively referred to as the skin microbiota—are fundamental to skin physiology and immunity. Interactions between skin microbes and the host can fall anywhere along the continuum between mutualism and pathogenicity. In this Review, we highlight how host–microbe interactions depend heavily on context, including the state of immune activation, host genetic predisposition, barrier status, microbe localization, and microbe–microbe interactions. We focus on how context shapes the complex dialogue between skin microbes and the host, and the consequences of this dialogue for health and disease.

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“…For example, of the CD4 + T cells present in the gastrointestinal tract of adult mice, 10% to 20% are Tregs (24), compared with 20% to 60% in skin. The majority of Tregs found in the GI tract are peripheral Tregs induced by commensal microbes, compared with Tregs in mouse skin, which appear to be thymus-derived and accumulate in the skin during a specific window of neonatal development (25).…”

Section: Cd8mentioning

confidence: 99%

Tissue-Specific Immunoregulation: A Call for Better Understanding of the “Immunostat” in the Context of Cancer

et al. 2018

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Checkpoint inhibitor therapy has been a breakthrough in cancer research, but only some patients with cancer derive substantial benefit. Although mechanisms underlying sensitivity and resistance to checkpoint inhibitors are being elucidated, the importance of organ-specific regulation of immunity is currently underappreciated. Here, we call for a greater understanding of tissue-specific immunoregulation, namely, “tissue-specific immunostats,” to make advances in treatments for cancer. A better understanding of how individual organs at baseline regulate the immune system could enable an improved precision medicine approach to cancer immunotherapy. Cancer Discov; 8(4); 395–402. ©2018 AACR.

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A Wave of Regulatory T Cells into Neonatal Skin Mediates Tolerance to Commensal Microbes

Cited by 447 publications

References 58 publications

Poly- N -Acetylglucosamine Production by Staphylococcus epidermidis Cells Increases Their In Vivo Proinflammatory Effect

Poly- N -Acetylglucosamine Production by Staphylococcus epidermidis Cells Increases Their In Vivo Proinflammatory Effect

Skin microbiota–host interactions

Tissue-Specific Immunoregulation: A Call for Better Understanding of the “Immunostat” in the Context of Cancer

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