21 results on '"Fassett MS"'
Search Results
2. Neuroimmune interactions in chronic itch of atopic dermatitis
- Author
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Yosipovitch, G, Berger, T, and Fassett, MS
- Subjects
Pain Research ,Eczema / Atopic Dermatitis ,Skin ,Chronic Disease ,Dermatitis ,Atopic ,Humans ,Keratinocytes ,Neuroimmunomodulation ,Pruritus ,Clinical Sciences ,Dermatology & Venereal Diseases - Abstract
Itch is a defining symptom of atopic dermatitis. Crosstalk between keratinocytes, the immune system and non-histaminergic sensory nerves is responsible for the pathophysiology of chronic itch in atopic dermatitis. An expanding understanding of the contribution of the nervous system and its interaction with immune pathways in atopic itch are helping to identify new therapeutic strategies.
- Published
- 2020
3. Transcriptional Programming of Normal and Inflamed Human Epidermis at Single-Cell Resolution
- Author
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Cheng, JB, Sedgewick, AJ, Finnegan, AI, Harirchian, P, Lee, J, Kwon, S, Fassett, MS, Golovato, J, Gray, M, Ghadially, R, Liao, W, Perez White, BE, Mauro, TM, Mully, T, Kim, EA, Sbitany, H, Neuhaus, IM, Grekin, RC, Yu, SS, Gray, JW, Purdom, E, Paus, R, Vaske, CJ, Benz, SC, Song, JS, and Cho, RJ
- Abstract
© 2018 The Authors Perturbations in the transcriptional programs specifying epidermal differentiation cause diverse skin pathologies ranging from impaired barrier function to inflammatory skin disease. However, the global scope and organization of this complex cellular program remain undefined. Here we report single-cell RNA sequencing profiles of 92,889 human epidermal cells from 9 normal and 3 inflamed skin samples. Transcriptomics-derived keratinocyte subpopulations reflect classic epidermal strata but also sharply compartmentalize epithelial functions such as cell-cell communication, inflammation, and WNT pathway modulation. In keratinocytes, ∼12% of assessed transcript expression varies in coordinate patterns, revealing undescribed gene expression programs governing epidermal homeostasis. We also identify molecular fingerprints of inflammatory skin states, including S100 activation in the interfollicular epidermis of normal scalp, enrichment of a CD1C+CD301A+myeloid dendritic cell population in psoriatic epidermis, and IL1βhiCCL3hiCD14+monocyte-derived macrophages enriched in foreskin. This compendium of RNA profiles provides a critical step toward elucidating epidermal diseases of development, differentiation, and inflammation. Cheng et al. report single-cell RNA sequencing of normal and inflamed human epidermis, revealing a discrete set of specialized keratinocytes that exhibit a distinct composition at different anatomic sites. Myeloid dendritic cells and macrophages also vary sharply with epidermal anatomic site and inflammation, indicating dynamic programming of antigen-presenting cells.
- Published
- 2018
4. An essential role for miR-15/16 in Treg suppression and restriction of proliferation.
- Author
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Johansson K, Gagnon JD, Zhou SK, Fassett MS, Schroeder AW, Kageyama R, Bautista RA, Pham H, Woodruff PG, and Ansel KM
- Subjects
- Animals, Mice, Cell Division, Phenotype, Inflammation genetics, Inflammation metabolism, Forkhead Transcription Factors metabolism, T-Lymphocytes, Regulatory, MicroRNAs genetics, MicroRNAs metabolism
- Abstract
The miR-15/16 family targets a large network of genes in T cells to restrict their cell cycle, memory formation, and survival. Upon T cell activation, miR-15/16 are downregulated, allowing rapid expansion of differentiated effector T cells to mediate a sustained response. Here, we used conditional deletion of miR-15/16 in regulatory T cells (Tregs) to identify immune functions of the miR-15/16 family in T cells. miR-15/16 are indispensable to maintain peripheral tolerance by securing efficient suppression by a limited number of Tregs. miR-15/16 deficiency alters expression of critical Treg proteins and results in accumulation of functionally impaired FOXP3
lo CD25lo CD127hi Tregs. Excessive proliferation in the absence of miR-15/16 shifts Treg fate and produces an effector Treg phenotype. These Tregs fail to control immune activation, leading to spontaneous multi-organ inflammation and increased allergic inflammation in a mouse model of asthma. Together, our results demonstrate that miR-15/16 expression in Tregs is essential to maintain immune tolerance., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2023
- Full Text
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5. IL-31-dependent neurogenic inflammation restrains cutaneous type 2 immune response in allergic dermatitis.
- Author
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Fassett MS, Braz JM, Castellanos CA, Salvatierra JJ, Sadeghi M, Yu X, Schroeder AW, Caston J, Munoz-Sandoval P, Roy S, Lazarevsky S, Mar DJ, Zhou CJ, Shin JS, Basbaum AI, and Ansel KM
- Subjects
- Animals, Mice, Cytokines, Immunity, Pyroglyphidae, Skin immunology, Interleukins immunology, Interleukins metabolism, Dermatitis, Atopic, Neurogenic Inflammation
- Abstract
Despite robust literature associating IL-31 with pruritic inflammatory skin diseases, its influence on cutaneous inflammation and the interplay between inflammatory and neurosensory pathways remain unmapped. Here, we examined the consequences of disrupting Il31 and its receptor Il31ra in a mouse model of house dust mite (HDM)-induced allergic dermatitis. Il31 -deficient mice displayed a deficit in HDM dermatitis-associated scratching, consistent with its well-established role as a pruritogen. In contrast, Il31 deficiency increased the number and proportion of cutaneous type 2 cytokine-producing CD4
+ T cells and serum IgE in response to HDM. Furthermore, Il4ra+ monocytes and macrophages capable of fueling a feedforward type 2 inflammatory loop were selectively enriched in Il31ra -deficient HDM dermatitis skin. Thus, IL-31 is not strictly a proinflammatory cytokine but rather an immunoregulatory factor that limits the magnitude of type 2 inflammatory responses in skin. Our data support a model wherein IL-31 activation of IL31RA+ pruritoceptors triggers release of calcitonin gene-related protein (CGRP), which can mediate neurogenic inflammation, inhibit CD4+ T cell proliferation, and reduce T cell production of the type 2 cytokine IL-13. Together, these results illustrate a previously unrecognized neuroimmune pathway that constrains type 2 tissue inflammation in the setting of chronic cutaneous allergen exposure and may explain paradoxical dermatitis flares in atopic patients treated with anti-IL31RA therapy.- Published
- 2023
- Full Text
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6. Can Serum Biomarkers for Prurigo Nodularis Expose Pathophysiology or Just Treatment Response?
- Author
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Kashem SW and Fassett MS
- Subjects
- Humans, Biomarkers, Prurigo diagnosis
- Published
- 2023
- Full Text
- View/download PDF
7. Innate type 2 immunity controls hair follicle commensalism by Demodex mites.
- Author
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Ricardo-Gonzalez RR, Kotas ME, O'Leary CE, Singh K, Damsky W, Liao C, Arouge E, Tenvooren I, Marquez DM, Schroeder AW, Cohen JN, Fassett MS, Lee J, Daniel SG, Bittinger K, Díaz RE, Fraser JS, Ali N, Ansel KM, Spitzer MH, Liang HE, and Locksley RM
- Subjects
- Animals, Cytokines, Hair Follicle pathology, Humans, Immunity, Innate, Inflammation, Interleukin-13, Lymphocytes pathology, Mice, Symbiosis, Mite Infestations complications, Mite Infestations parasitology, Mite Infestations pathology, Mites
- Abstract
Demodex mites are commensal parasites of hair follicles (HFs). Normally asymptomatic, inflammatory outgrowth of mites can accompany malnutrition, immune dysfunction, and aging, but mechanisms restricting Demodex outgrowth are not defined. Here, we show that control of mite HF colonization in mice required group 2 innate lymphoid cells (ILC2s), interleukin-13 (IL-13), and its receptor, IL-4Ra-IL-13Ra1. HF-associated ILC2s elaborated IL-13 that attenuated HFs and epithelial proliferation at anagen onset; in their absence, Demodex colonization led to increased epithelial proliferation and replacement of gene programs for repair by aberrant inflammation, leading to the loss of barrier function and HF exhaustion. Humans with rhinophymatous acne rosacea, an inflammatory condition associated with Demodex, had increased HF inflammation with decreased type 2 cytokines, consistent with the inverse relationship seen in mice. Our studies uncover a key role for skin ILC2s and IL-13, which comprise an immune checkpoint that sustains cutaneous integrity and restricts pathologic infestation by colonizing HF mites., Competing Interests: Declaration of interests R.M.L. is a member of the Scientific Resource Board at Genentech and serves on the Advisory Board at Immunity., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
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8. Evaluation of Gabapentin and Transforaminal Corticosteroid Injections for Brachioradial Pruritus.
- Author
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Gutierrez RA, Berger TG, Shah V, Agnihothri R, Demir-Deviren S, and Fassett MS
- Subjects
- Adrenal Cortex Hormones, Gabapentin, Humans, Cervical Vertebrae, Pruritus drug therapy, Pruritus etiology
- Published
- 2022
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9. Cutaneous Pathology of COVID-19 as a Window into Immunologic Mechanisms of Disease.
- Author
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Gallman AE and Fassett MS
- Subjects
- Chilblains physiopathology, Erythema Multiforme physiopathology, Exanthema physiopathology, Humans, Pityriasis Rosea physiopathology, Skin physiopathology, Skin Diseases, Vesiculobullous physiopathology, COVID-19 physiopathology, Skin Diseases physiopathology
- Abstract
Many skin manifestations of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection reflect activation of cutaneous and systemic immune responses involving effector pathways of both the innate and adaptive arms of the immune system. This article reviews evidence from the recent clinical and scientific literature that informs the current understanding of the consequences of coronavirus disease 2019 (COVID-19)-induced immune cell activation, as relevant to dermatology. Topics include the clinical consequences of autoantibody production in patients with COVID-19, immunologic evidence for chilblains as a manifestation of SARS-CoV-2 infection, and the relationship between type I interferons and COVID-19 disease severity., (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Published
- 2021
- Full Text
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10. Long COVID in the skin: a registry analysis of COVID-19 dermatological duration.
- Author
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McMahon DE, Gallman AE, Hruza GJ, Rosenbach M, Lipoff JB, Desai SR, French LE, Lim H, Cyster JG, Fox LP, Fassett MS, and Freeman EE
- Subjects
- Adult, COVID-19 immunology, COVID-19 pathology, COVID-19 virology, Female, Humans, Male, Middle Aged, Skin Diseases immunology, Skin Diseases pathology, Young Adult, COVID-19 diagnosis, SARS-CoV-2 isolation & purification, Skin virology, Skin Diseases diagnosis, Skin Diseases virology
- Published
- 2021
- Full Text
- View/download PDF
11. Genetic priming of sensory neurons in mice that overexpress PAR2 enhances allergen responsiveness.
- Author
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Braz JM, Dembo T, Charruyer A, Ghadially R, Fassett MS, and Basbaum AI
- Subjects
- Animals, Dermatitis, Atopic chemically induced, Dermatitis, Atopic metabolism, Disease Models, Animal, Mice, Mice, Transgenic, RNA-Seq, Receptor, PAR-2 genetics, Sensory Receptor Cells drug effects, Sensory Receptor Cells metabolism, Skin drug effects, Skin innervation, Skin metabolism, Allergens toxicity, DNA-Binding Proteins physiology, Dermatitis, Atopic pathology, Receptor, PAR-2 metabolism, Sensory Receptor Cells pathology, Skin pathology, Transcription Factors physiology
- Abstract
Pruritus is a common symptom of inflammatory skin conditions, including atopic dermatitis (AD). Although primary sensory neurons that transmit pruritic signals are well-cataloged, little is known about the neuronal alterations that occur as a result of skin disruption in AD. To address this question, we examined the molecular and behavioral consequences of challenging Grhl3
PAR2/+ mice, which overexpress PAR2 in suprabasal keratinocytes, with serial topical application of the environmental allergen house dust mite (HDM). We monitored behavior and used RNA sequencing, qPCR, and in situ hybridization to evaluate gene expression in trigeminal ganglia (TG), before and after HDM. We found that neither Grhl3PAR2/+ nor wild-type (WT) mice exhibited spontaneous scratching, and pruritogen-induced acute scratching did not differ. In contrast, HDM exacerbated scratching in Grhl3PAR2/+ mice. Despite the absence of scratching in untreated Grhl3PAR2/+ mice, several TG genes in these mice were up-regulated compared to WT. HDM treatment of the Grhl3PAR2/+ mice enhanced up-regulation of this set of genes and induced additional genes, many within the subset of TG neurons that express TRPV1. The same set of genes was up-regulated in HDM-treated Grhl3PAR2/+ mice that did not scratch, but at lesser magnitude. Finally, we recorded comparable transcriptional changes in IL31Tg mice, demonstrating that a common genetic program is induced in two AD models. Taken together, we conclude that transcriptional changes that occur in primary sensory neurons in dermatitis-susceptible animals underlie a genetic priming that not only sensitizes the animal to chronic allergens but also contributes to pruritus in atopic skin disease., Competing Interests: The authors declare no competing interest.- Published
- 2021
- Full Text
- View/download PDF
12. Timing of PCR and antibody testing in patients with COVID-19-associated dermatologic manifestations.
- Author
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Freeman EE, McMahon DE, Hruza GJ, Lipoff JB, French LE, Fox LP, and Fassett MS
- Subjects
- Humans, Time Factors, COVID-19 complications, COVID-19 diagnosis, COVID-19 Nucleic Acid Testing, Skin Diseases etiology
- Published
- 2021
- Full Text
- View/download PDF
13. Single-Cell Profiling Reveals Divergent, Globally Patterned Immune Responses in Murine Skin Inflammation.
- Author
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Liu Y, Cook C, Sedgewick AJ, Zhang S, Fassett MS, Ricardo-Gonzalez RR, Harirchian P, Kashem SW, Hanakawa S, Leistico JR, North JP, Taylor MA, Zhang W, Man MQ, Charruyer A, Beliakova-Bethell N, Benz SC, Ghadially R, Mauro TM, Kaplan DH, Kabashima K, Choi J, Song JS, Cho RJ, and Cheng JB
- Abstract
Inflammatory response heterogeneity has impeded high-resolution dissection of diverse immune cell populations during activation. We characterize mouse cutaneous immune cells by single-cell RNA sequencing, after inducing inflammation using imiquimod and oxazolone dermatitis models. We identify 13 CD45
+ subpopulations, which broadly represent most functionally characterized immune cell types. Oxazolone pervasively upregulates Jak2 / Stat3 expression across T cells and antigen-presenting cells (APCs). Oxazolone also induces Il4 / Il13 expression in newly infiltrating basophils, and Il4ra and Ccl24, most prominently in APCs. In contrast, imiquimod broadly upregulates Il17 / Il22 and Ccl4 / Ccl5 . A comparative analysis of single-cell inflammatory transcriptional responses reveals that APC response to oxazolone is tightly restricted by cell identity, whereas imiquimod enforces shared programs on multiple APC populations in parallel. These global molecular patterns not only contrast immune responses on a systems level but also suggest that the mechanisms of new sources of inflammation can eventually be deduced by comparison to known signatures., Competing Interests: A.J.S. and S.C.B. are employees of ImmunityBio Inc, S.C.B. is an equity holder of ImmunityBio Inc. The remaining authors disclose no conflicts.- Published
- 2020
- Full Text
- View/download PDF
14. Treatment of PD-1/PD-L1 Inhibitor-Induced Dermatitis Resolves Concomitant Eruptive Keratoacanthomas.
- Author
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Crow LD, Perkins I, Twigg AR, Fassett MS, LeBoit PE, Berger TG, and Khodosh R
- Subjects
- Aged, Antineoplastic Agents, Immunological administration & dosage, B7-H1 Antigen antagonists & inhibitors, Drug Eruptions drug therapy, Female, Humans, Immunotherapy adverse effects, Immunotherapy methods, Keratoacanthoma drug therapy, Male, Programmed Cell Death 1 Receptor antagonists & inhibitors, Treatment Outcome, Anti-Inflammatory Agents administration & dosage, Antineoplastic Agents, Immunological adverse effects, Drug Eruptions etiology, Keratoacanthoma etiology
- Published
- 2020
- Full Text
- View/download PDF
15. miR-15/16 Restrain Memory T Cell Differentiation, Cell Cycle, and Survival.
- Author
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Gagnon JD, Kageyama R, Shehata HM, Fassett MS, Mar DJ, Wigton EJ, Johansson K, Litterman AJ, Odorizzi P, Simeonov D, Laidlaw BJ, Panduro M, Patel S, Jeker LT, Feeney ME, McManus MT, Marson A, Matloubian M, Sanjabi S, and Ansel KM
- Subjects
- Animals, Antigens metabolism, Cell Survival genetics, Gene Expression Regulation, Gene Regulatory Networks, Genetic Loci, Lymphocytic choriomeningitis virus physiology, Mice, Transgenic, MicroRNAs genetics, Cell Cycle genetics, Cell Differentiation genetics, Immunologic Memory, MicroRNAs metabolism, T-Lymphocytes cytology, T-Lymphocytes immunology
- Abstract
Coordinate control of T cell proliferation, survival, and differentiation are essential for host protection from pathogens and cancer. Long-lived memory cells, whose precursors are formed during the initial immunological insult, provide protection from future encounters, and their generation is the goal of many vaccination strategies. microRNAs (miRNAs) are key nodes in regulatory networks that shape effective T cell responses through the fine-tuning of thousands of genes. Here, using compound conditional mutant mice to eliminate miR-15/16 family miRNAs in T cells, we show that miR-15/16 restrict T cell cycle, survival, and memory T cell differentiation. High throughput sequencing of RNA isolated by cross-linking immunoprecipitation of AGO2 combined with gene expression analysis in miR-15/16-deficient T cells indicates that these effects are mediated through the direct inhibition of an extensive network of target genes within pathways critical to cell cycle, survival, and memory., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
16. Transcriptional Programming of Normal and Inflamed Human Epidermis at Single-Cell Resolution.
- Author
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Cheng JB, Sedgewick AJ, Finnegan AI, Harirchian P, Lee J, Kwon S, Fassett MS, Golovato J, Gray M, Ghadially R, Liao W, Perez White BE, Mauro TM, Mully T, Kim EA, Sbitany H, Neuhaus IM, Grekin RC, Yu SS, Gray JW, Purdom E, Paus R, Vaske CJ, Benz SC, Song JS, and Cho RJ
- Subjects
- Amphiregulin pharmacology, Biomarkers metabolism, Cell Aggregation genetics, Cell Communication, Cell Differentiation, Cell Proliferation, Foreskin cytology, Hair Follicle metabolism, Humans, Inflammation immunology, Keratinocytes metabolism, Kinetics, Male, Psoriasis genetics, Psoriasis immunology, Psoriasis pathology, S100 Proteins metabolism, Time Factors, Transcriptome genetics, Wnt Proteins metabolism, Epidermis metabolism, Epidermis pathology, Inflammation genetics, Inflammation pathology, Single-Cell Analysis, Transcription, Genetic
- Abstract
Perturbations in the transcriptional programs specifying epidermal differentiation cause diverse skin pathologies ranging from impaired barrier function to inflammatory skin disease. However, the global scope and organization of this complex cellular program remain undefined. Here we report single-cell RNA sequencing profiles of 92,889 human epidermal cells from 9 normal and 3 inflamed skin samples. Transcriptomics-derived keratinocyte subpopulations reflect classic epidermal strata but also sharply compartmentalize epithelial functions such as cell-cell communication, inflammation, and WNT pathway modulation. In keratinocytes, ∼12% of assessed transcript expression varies in coordinate patterns, revealing undescribed gene expression programs governing epidermal homeostasis. We also identify molecular fingerprints of inflammatory skin states, including S100 activation in the interfollicular epidermis of normal scalp, enrichment of a CD1C
+ CD301A+ myeloid dendritic cell population in psoriatic epidermis, and IL1βhi CCL3hi CD14+ monocyte-derived macrophages enriched in foreskin. This compendium of RNA profiles provides a critical step toward elucidating epidermal diseases of development, differentiation, and inflammation., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2018
- Full Text
- View/download PDF
17. Identification of Functionally Relevant microRNAs in the Regulation of Allergic Inflammation.
- Author
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Fassett MS, Pua HH, Simpson LJ, Steiner DF, and Ansel KM
- Subjects
- Animals, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes metabolism, Electroporation, Gene Expression, Hypersensitivity immunology, Lymphocyte Activation, Mice, T-Lymphocytes immunology, T-Lymphocytes metabolism, Hypersensitivity genetics, MicroRNAs genetics
- Abstract
Transgenic methods to manipulate CD4 T lymphocytes in vivo via forced expression of TCR transgenes and targeted "knockout" of individual genes by Cre-lox technology are fundamental to modern immunology. However, efforts to scale up functional analysis by modifying expression of larger numbers of genes in T cells ex vivo have proven surprisingly difficult. Early RNA interference experiments achieved successful small RNA transfection by using very high concentrations of short-interfering RNA (siRNA) [1], but primary T cells are generally resistant to standard electroporation, cationic liposome-, and calcium phosphate-mediated transfection methods. Moreover, although viral vectors can successfully introduce DNA fragments of varying length, expression of these constructs in primary T cells is low efficiency and the subcloning process laborious. In this context, the relatively recent discovery of dozens of highly expressed microRNAs (miRNAs) in the immune system provides both an opportunity and a new challenge [2, 3]. How can we query the miRNAome of a cell to assign particular roles to individual miRNAs? Here, we describe an optimized technique for efficient and reproducible transfection of primary mouse CD4 T cells in vitro with synthetic miRNA mimics.
- Published
- 2018
- Full Text
- View/download PDF
18. A multiply redundant genetic switch 'locks in' the transcriptional signature of regulatory T cells.
- Author
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Fu W, Ergun A, Lu T, Hill JA, Haxhinasto S, Fassett MS, Gazit R, Adoro S, Glimcher L, Chan S, Kastner P, Rossi D, Collins JJ, Mathis D, and Benoist C
- Subjects
- Animals, CD4 Antigens biosynthesis, Cell Differentiation, Computational Biology, DNA-Binding Proteins biosynthesis, DNA-Binding Proteins genetics, Forkhead Transcription Factors genetics, GATA1 Transcription Factor genetics, Humans, Ikaros Transcription Factor biosynthesis, Ikaros Transcription Factor genetics, Interferon Regulatory Factors genetics, Lymphocyte Activation, Lymphoid Enhancer-Binding Factor 1 genetics, Matrix Attachment Region Binding Proteins genetics, Mice, Mice, Inbred C57BL, Regulatory Factor X Transcription Factors, Serine Endopeptidases genetics, T-Lymphocytes, Regulatory cytology, Transcription Factors biosynthesis, Transcription Factors genetics, X-Box Binding Protein 1, T-Lymphocytes, Regulatory immunology, T-Lymphocytes, Regulatory metabolism, Transcription Factors metabolism, Transcription, Genetic
- Abstract
The transcription factor Foxp3 participates dominantly in the specification and function of Foxp3(+)CD4(+) regulatory T cells (T(reg) cells) but is neither strictly necessary nor sufficient to determine the characteristic T(reg) cell signature. Here we used computational network inference and experimental testing to assess the contribution of other transcription factors to this. Enforced expression of Helios or Xbp1 elicited distinct signatures, but Eos, IRF4, Satb1, Lef1 and GATA-1 elicited exactly the same outcome, acting in synergy with Foxp3 to activate expression of most of the T(reg) cell signature, including key transcription factors, and enhancing occupancy by Foxp3 at its genomic targets. Conversely, the T(reg) cell signature was robust after inactivation of any single cofactor. A redundant genetic switch thus 'locked in' the T(reg) cell phenotype, a model that would account for several aspects of T(reg) cell physiology, differentiation and stability.
- Published
- 2012
- Full Text
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19. Nuclear receptor Nr4a1 modulates both regulatory T-cell (Treg) differentiation and clonal deletion.
- Author
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Fassett MS, Jiang W, D'Alise AM, Mathis D, and Benoist C
- Subjects
- Animals, Apoptosis, Apoptosis Regulatory Proteins metabolism, Bcl-2-Like Protein 11, Cell Differentiation, Cell Lineage, Cell Nucleus metabolism, Glycolysis, Membrane Proteins metabolism, Mice, Mice, Knockout, Nuclear Receptor Subfamily 4, Group A, Member 1 genetics, Peptides chemistry, Proto-Oncogene Proteins metabolism, Thymocytes cytology, Time Factors, Transcription Factors metabolism, Nuclear Receptor Subfamily 4, Group A, Member 1 physiology, T-Lymphocytes, Regulatory cytology
- Abstract
Immature thymocytes expressing autoreactive T-cell receptors (TCR) can adopt differing cell fates: clonal deletion by apoptosis or deviation into alternative lineages such as FoxP3(+) regulatory T cells (Treg). We revisited the role of the transcription factor Nr4a1 (Nur77), an immediate-early response gene induced by TCR engagement. Nr4a1KO mice show clear quantitative defects in antigen-induced clonal deletion. The impact of the Nr4a1 deletion is not enhanced by deletion of the proapoptotic factor Bim. In addition, Nr4a1 curtails initial differentiation into the Treg lineage in TCR transgenic mice and in nontransgenic mice. Transcriptional profiling of Nr4a1KO thymocytes under selection conditions reveals that Nr4a1 activates the transcription of several targets, consistent with these diverse actions: (i) Nr4a1 partakes in the induction of Bim after TCR triggering; (ii) perhaps paradoxically, Nr4a1 positively controls several transcripts of the Treg signature, in particular Ikzf2 and Tnfrsf9; (iii) consistent with its prosurvival and metabolic role in the liver, Nr4a1 is also required for the induction by TCR of a coordinated set of enzymes of the glycolytic and Krebs cycle pathways, which we propose may antagonize Treg selection as does activation of mTOR/Akt. Thus, Nr4a1 appears to act as a balancing molecule in fate determination at a critical juncture of T-cell differentiation.
- Published
- 2012
- Full Text
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20. Viral evasion of natural killer cells.
- Author
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Orange JS, Fassett MS, Koopman LA, Boyson JE, and Strominger JL
- Subjects
- Animals, Antigens, Viral genetics, Antigens, Viral immunology, Chemokines physiology, Cytokines genetics, Cytokines physiology, Cytotoxicity, Immunologic, Down-Regulation, Gene Expression Regulation, Viral, Genes, MHC Class I, Histocompatibility Antigens Class I immunology, Humans, Killer Cells, Natural virology, Mice, Models, Immunological, Receptors, Immunologic genetics, Receptors, Immunologic physiology, Virus Diseases immunology, Viruses genetics, Killer Cells, Natural immunology, Viruses immunology
- Abstract
Viruses have evolved mechanisms to avoid the host immune system, including means of escaping detection by both the innate and adaptive immune responses. Natural killer (NK) cells are a central component of the innate immune system and are crucial in defense against certain viruses. To attain a state of chronic infection, some successful viruses have developed specific mechanisms to evade detection by and activation of NK cells. These NK cell-specific evasion mechanisms fall into distinct mechanistic categories used in numerous virus families.
- Published
- 2002
- Full Text
- View/download PDF
21. Signaling at the inhibitory natural killer cell immune synapse regulates lipid raft polarization but not class I MHC clustering.
- Author
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Fassett MS, Davis DM, Valter MM, Cohen GB, and Strominger JL
- Subjects
- Animals, Cell Line, Cytoskeleton drug effects, Cytoskeleton metabolism, Humans, Mice, Mutagenesis, Site-Directed, Protein Structure, Tertiary, Receptors, Immunologic chemistry, Receptors, Immunologic genetics, Receptors, Immunologic metabolism, Receptors, KIR2DL1, Signal Transduction, Transfection, Histocompatibility Antigens Class I metabolism, Killer Cells, Natural immunology, Killer Cells, Natural metabolism, Membrane Microdomains metabolism
- Abstract
Natural killer (NK) cell cytotoxicity is determined by a balance of positive and negative signals. Negative signals are transmitted by NK inhibitory receptors (killer immunoglobulin-like receptors, KIR) at the site of membrane apposition between an NK cell and a target cell, where inhibitory receptors become clustered with class I MHC ligands in an organized structure known as an inhibitory NK immune synapse. Immune synapse formation in NK cells is poorly understood. Because signaling by NK inhibitory receptors could be involved in this process, the human NK tumor line YTS was transfected with signal-competent and signal-incompetent KIR2DL1. The latter were generated by truncating the KIR2DL1 cytoplasmic tail or by introducing mutations in the immunoreceptor tyrosine-based inhibition motifs. The KIR2DL1 mutants retained their ability to cluster class I MHC ligands on NK cell interaction with appropriate target cells. Therefore, receptor-ligand clustering at the inhibitory NK immune synapse occurs independently of KIR2DL1 signal transduction. However, parallel examination of NK cell membrane lipid rafts revealed that KIR2DL1 signaling is critical for blocking lipid raft polarization and NK cell cytotoxicity. Moreover, raft polarization was inhibited by reagents that disrupt microtubules and actin filaments, whereas synapse formation was not. Thus, NK lipid raft polarization and inhibitory NK immune synapse formation occur by fundamentally distinct mechanisms.
- Published
- 2001
- Full Text
- View/download PDF
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