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1.
J Am Acad Dermatol ; 77(3): 417-424, 2017 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-28624119

RESUMEN

BACKGROUND: Evidence from adult psoriasis studies implicates an imbalance between regulatory and effector T cells, particularly TH-17-producing T cells, in the pathogenesis of psoriasis. Little is known about the immunopathology of psoriasis in children. OBJECTIVE: We sought to functionally characterize the inflammatory cell profiles of psoriatic plaques from pediatric patients and compare them with healthy, age-matched controls and adult psoriasis patients. METHODS: Skin samples from pediatric psoriasis patients and healthy controls were analyzed by multiparameter flow cytometry to determine the dominant immune cell subsets present and cytokines produced. RESULTS: Lesional tissue from pediatric psoriasis patients had significantly increased interleukin (IL) 22 derived from CD4+ and CD8+ cells compared with the tissues from healthy pediatric controls and adult psoriasis patients. Tissue from pediatric psoriasis patients had significantly less elevation of IL-17 derived from CD4+ and CD8+ cells compared with the tissue from adult psoriasis patients. In contrast with the lesions from adult patients, lesional skin in pediatric patients with psoriasis did not have increases in regulatory T cells. LIMITATIONS: This is a pilot study, thus the sample size is small. CONCLUSION: Significant differences in IL-17 and IL-22 expression were observed in the pediatric psoriasis patients compared with pediatric healthy controls and adult psoriasis patients. IL-22 might be relevant in the pathogenesis of pediatric psoriasis and represents a potential treatment target unique to pediatric psoriasis.


Asunto(s)
Interleucina-17/biosíntesis , Interleucinas/biosíntesis , Psoriasis/inmunología , Psoriasis/patología , Linfocitos T/inmunología , Linfocitos T/metabolismo , Adolescente , Adulto , Factores de Edad , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Proyectos Piloto , Interleucina-22
2.
bioRxiv ; 2022 Mar 16.
Artículo en Inglés | MEDLINE | ID: mdl-35313585

RESUMEN

Many studies have provided insights into the immune response to COVID-19; however, little is known about the immunological changes and immune signaling occurring during COVID-19 resolution. Individual heterogeneity and variable disease resolution timelines obscure unifying immune characteristics. Here, we collected and profiled >200 longitudinal peripheral blood samples from patients hospitalized with COVID-19, with other respiratory infections, and healthy individuals, using mass cytometry to measure immune cells and signaling states at single cell resolution. COVID-19 patients showed a unique immune composition and an early, coordinated and elevated immune cell signaling profile, which correlated with early hospital discharge. Intra-patient time course analysis tied to clinically relevant events of recovery revealed a conserved set of immunological processes that accompany, and are unique to, disease resolution and discharge. This immunological process, together with additional changes in CD4 regulatory T cells and basophils, accompanies recovery from respiratory failure and is associated with better clinical outcomes at the time of admission. Our work elucidates the biological timeline of immune recovery from COVID-19 and provides insights into the fundamental processes of COVID-19 resolution in hospitalized patients.

3.
Sci Immunol ; 4(39)2019 09 06.
Artículo en Inglés | MEDLINE | ID: mdl-31492709

RESUMEN

At the center of fibrosing diseases is the aberrant activation of tissue fibroblasts. The cellular and molecular mechanisms of how the immune system augments fibroblast activation have been described; however, little is known about how the immune system controls fibroblast function in tissues. Here, we identify regulatory T cells (Tregs) as important regulators of fibroblast activation in skin. Bulk cell and single-cell analysis of Tregs in murine skin and lungs revealed that Tregs in skin are transcriptionally distinct and skewed toward T helper 2 (TH2) differentiation. When compared with Tregs in lung, skin Tregs preferentially expressed high levels of GATA3, the master TH2 transcription factor. Genes regulated by GATA3 were highly enriched in skin "TH2 Treg" subsets. In functional experiments, Treg depletion resulted in a preferential increase in TH2 cytokine production in skin. Both acute depletion and chronic reduction of Tregs resulted in spontaneous skin fibroblast activation, profibrotic gene expression, and dermal fibrosis, all of which were exacerbated in a bleomycin-induced murine model of skin sclerosis. Lineage-specific deletion of Gata3 in Tregs resulted in an exacerbation of TH2 cytokine secretion that was preferential to skin, resulting in enhanced fibroblast activation and dermal fibrosis. Together, we demonstrate that Tregs play a critical role in regulating fibroblast activation in skin and do so by expressing a unique tissue-restricted transcriptional program that is mediated, at least in part, by GATA3.


Asunto(s)
Fibroblastos/inmunología , Piel/inmunología , Linfocitos T Reguladores/inmunología , Animales , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos
4.
Sci Immunol ; 3(30)2018 12 21.
Artículo en Inglés | MEDLINE | ID: mdl-30578350

RESUMEN

Regulatory T cells (Tregs) are closely related to TH17 cells and use aspects of the TH17-differentiation program for optimal immune regulation. In several chronic inflammatory human diseases, Tregs express IL-17A, suggesting that dysregulation of TH17-associated pathways in Tregs may result in either loss of suppressive function and/or conversion into pathogenic cells. The pathways that regulate the TH17 program in Tregs are poorly understood. We have identified two TNF receptor superfamily (TNFRSF) members, CD27 and OX40, that are preferentially expressed by skin-resident Tregs Both CD27 and OX40 signaling suppressed the expression of TH17-associated genes from Tregs in a cell-intrinsic manner in vitro and in vivo. However, only OX40 played a nonredundant role in promoting Treg accumulation. Tregs that lacked both CD27 and OX40 were defective in controlling skin inflammation and expressed high levels of IL-17A, as well as the master TH17 transcription factor, RORγt. Last, we found that CD27 expression was inversely correlated with Treg IL-17 production in skin of patients with psoriasis and hidradenitis suppurativa. Together, our results suggest that TNFRSF members play both redundant and distinct roles in regulating Treg plasticity in tissues.


Asunto(s)
Glicoproteínas de Membrana/inmunología , Linfocitos T Reguladores/inmunología , Células Th17/inmunología , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/inmunología , Factores de Necrosis Tumoral/inmunología , Animales , Diferenciación Celular/inmunología , Glicoproteínas de Membrana/deficiencia , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ligando OX40 , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/deficiencia , Factores de Necrosis Tumoral/deficiencia
5.
J Clin Invest ; 126(9): 3447-52, 2016 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-27525433

RESUMEN

BACKGROUND: Immune checkpoint blockade is revolutionizing therapy for advanced cancer, but many patients do not respond to treatment. The identification of robust biomarkers that predict clinical response to specific checkpoint inhibitors is critical in order to stratify patients and to rationally select combinations in the context of an expanding array of therapeutic options. METHODS: We performed multiparameter flow cytometry on freshly isolated metastatic melanoma samples from 2 cohorts of 20 patients each prior to treatment and correlated the subsequent clinical response with the tumor immune phenotype. RESULTS: Increasing fractions of programmed cell death 1 high/cytotoxic T lymphocyte-associated protein 4 high (PD-1hiCTLA-4hi) cells within the tumor-infiltrating CD8+ T cell subset strongly correlated with response to therapy (RR) and progression-free survival (PFS). Functional analysis of these cells revealed a partially exhausted T cell phenotype. Assessment of metastatic lesions during anti-PD-1 therapy demonstrated a release of T cell exhaustion, as measured by an accumulation of highly activated CD8+ T cells within tumors, with no effect on Tregs. CONCLUSIONS: Our data suggest that the relative abundance of partially exhausted tumor-infiltrating CD8+ T cells predicts response to anti-PD-1 therapy. This information can be used to appropriately select patients with a high likelihood of achieving a clinical response to PD-1 pathway inhibition. FUNDING: This work was funded by a generous gift provided by Inga-Lill and David Amoroso as well as a generous gift provided by Stephen Juelsgaard and Lori Cook.


Asunto(s)
Melanoma/inmunología , Melanoma/metabolismo , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/metabolismo , Anticuerpos Monoclonales Humanizados/administración & dosificación , Biopsia , Linfocitos T CD8-positivos/citología , Antígeno CTLA-4/metabolismo , Línea Celular Tumoral , Estudios de Cohortes , Femenino , Citometría de Flujo , Humanos , Sistema Inmunológico , Antígenos Comunes de Leucocito/metabolismo , Activación de Linfocitos/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Masculino , Melanoma/patología , Metástasis de la Neoplasia , Fenotipo , Receptor de Muerte Celular Programada 1/metabolismo , Neoplasias Cutáneas/patología , Subgrupos de Linfocitos T/citología , Microambiente Tumoral/inmunología
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