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The Role of Autophagy in iNKT Cell Development.
Yang G, Driver JP, Van Kaer L
(2018) Front Immunol 9: 2653
MeSH Terms: Animals, Autophagy, Cell Differentiation, Humans, Natural Killer T-Cells, Receptors, Antigen, T-Cell, alpha-beta, Thymus Gland
Show Abstract · Added March 26, 2019
CD1d-restricted invariant natural killer T (iNKT) cells are innate-like T cells that express an invariant T cell receptor (TCR) α-chain and recognize self and foreign glycolipid antigens. They can rapidly respond to agonist activation and stimulate an extensive array of immune responses. Thymic development and function of iNKT cells are regulated by many different cellular processes, including autophagy, a self-degradation mechanism. In this mini review, we discuss the current understanding of how autophagy regulates iNKT cell development and effector lineage differentiation. Importantly, we propose that iNKT cell development is tightly controlled by metabolic reprogramming.
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7 MeSH Terms
Characterization of nitrogen mustard formamidopyrimidine adduct formation of bis(2-chloroethyl)ethylamine with calf thymus DNA and a human mammary cancer cell line.
Gruppi F, Hejazi L, Christov PP, Krishnamachari S, Turesky RJ, Rizzo CJ
(2015) Chem Res Toxicol 28: 1850-60
MeSH Terms: Animals, Cattle, Cell Line, Tumor, DNA, Humans, Mechlorethamine, Nitrogen Mustard Compounds, Pyrimidines, Thymus Gland
Show Abstract · Added January 7, 2016
A robust, quantitative ultraperformance liquid chromatography ion trap multistage scanning mass spectrometric (UPLC/MS(3)) method was established to characterize and measure five guanine adducts formed by reaction of the chemotherapeutic nitrogen mustard (NM) bis(2-chloroethyl)ethylamine with calf thymus (CT) DNA. In addition to the known N7-guanine (NM-G) adduct and its cross-link (G-NM-G), the ring-opened formamidopyrimidine (FapyG) monoadduct (NM-FapyG) and cross-links in which one (FapyG-NM-G) or both (FapyG-NM-FapyG) guanines underwent ring-opening to FapyG units were identified. Authentic standards of all adducts were synthesized and characterized by NMR and mass spectrometry. These adducts were quantified in CT DNA treated with NM (1 μM) as their deglycosylated bases. A two-stage neutral thermal hydrolysis was developed to mitigate the artifactual formation of ring-opened FapyG adducts involving hydrolysis of the cationic adduct at 37 °C, followed by hydrolysis of the FapyG adducts at 95 °C. The limit of quantification values ranged between 0.3 and 1.6 adducts per 10(7) DNA bases when the equivalent of 5 μg of DNA hydrolysate was assayed on column. The principal adduct formed was the G-NM-G cross-link, followed by the NM-G monoadduct; the FapyG-NM-G cross-link adduct; and the FapyG-NM-FapyG was below the limit of detection. The NM-FapyG adducts were formed in CT DNA at a level ∼20% that of the NM-G adduct. NM-FapyG has not been previously quanitified, and the FapyG-NM-G and FapyG-NM-FapyG adducts have not been previously characterized. Our validated analytical method was then applied to measure DNA adduct formation in the MDA-MB-231 mammary tumor cell line exposed to NM (100 μM) for 24 h. The major adduct formed was NM-G (970 adducts per 10(7) bases), followed by G-NM-G (240 adducts per 10(7) bases), NM-FapyG (180 adducts per 10(7) bases), and, last, the FapyG-NM-G cross-link adduct (6.0 adducts per 10(7) bases). These lesions are expected to contribute to NM-mediated toxicity and genotoxicity in vivo.
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9 MeSH Terms
Histone Deacetylase 3 Is Required for T Cell Maturation.
Hsu FC, Belmonte PJ, Constans MM, Chen MW, McWilliams DC, Hiebert SW, Shapiro VS
(2015) J Immunol 195: 1578-90
MeSH Terms: Animals, Bone Marrow Cells, Cell Differentiation, Cell Movement, Complement Activation, Complement System Proteins, Histone Deacetylases, Homeostasis, Interleukin-7, Lymphocyte Count, Mice, Mice, Knockout, Mice, Transgenic, T-Lymphocyte Subsets, T-Lymphocytes, Thymus Gland, Tumor Necrosis Factors
Show Abstract · Added September 28, 2015
Recent thymic emigrants are newly generated T cells that need to undergo postthymic maturation to gain functional competency and enter the long-lived naive T cell pool. The mechanism of T cell maturation remains incompletely understood. Previously, we demonstrated that the transcriptional repressor NKAP is required for T cell maturation. Because NKAP associates with histone deacetylase 3 (HDAC3), we examined whether HDAC3 is also required for T cell maturation. Although thymic populations are similar in CD4-cre HDAC3 conditional knockout mice compared with wild-type mice, the peripheral numbers of CD4(+) and CD8(+) T cells are dramatically decreased. In the periphery, the majority of HDAC3-deficient naive T cells are recent thymic emigrants, indicating a block in T cell maturation. CD55 upregulation during T cell maturation is substantially decreased in HDAC3-deficient T cells. Consistent with a block in functional maturation, HDAC3-deficient peripheral T cells have a defect in TNF licensing after TCR/CD28 stimulation. CD4-cre HDAC3 conditional knockout mice do not have a defect in intrathymic migration, thymic egress, T cell survival, or homeostasis. In the periphery, similar to immature NKAP-deficient peripheral T cells, HDAC3-deficient peripheral T cells were bound by IgM and complement proteins, leading to the elimination of these cells. In addition, HDAC3-deficient T cells display decreases in the sialic acid modifications on the cell surface that recruit natural IgM to initiate the classical complement pathway. Therefore, HDAC3 is required for T cell maturation.
Copyright © 2015 by The American Association of Immunologists, Inc.
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17 MeSH Terms
A randomized controlled trial of palifermin (recombinant human keratinocyte growth factor) for the treatment of inadequate CD4+ T-lymphocyte recovery in patients with HIV-1 infection on antiretroviral therapy.
Jacobson JM, Wang H, Bordi R, Zheng L, Gross BH, Landay AL, Spritzler J, Routy JP, Benson C, Aberg J, Tebas P, Haas DW, Tiu J, Coughlin K, Purdue L, Sekaly RP, AIDS Clinical Trials Group (ACTG) A5212 Protocol Team
(2014) J Acquir Immune Defic Syndr 66: 399-406
MeSH Terms: Adult, Anti-HIV Agents, CD4 Lymphocyte Count, Dose-Response Relationship, Drug, Double-Blind Method, Female, Fibroblast Growth Factor 7, HIV Infections, HIV-1, Humans, Male, Middle Aged, RNA, Viral, Recombinant Proteins, Thymus Gland, Viral Load
Show Abstract · Added March 13, 2015
BACKGROUND - Poor CD4 lymphocyte recovery on antiretroviral therapy (ART) is associated with reduced function of the thymus. Palifermin (keratinocyte growth factor), by providing support to the thymic epithelium, promotes lymphopoiesis in animal models of bone marrow transplantation and graft-versus-host disease.
METHODS - In AIDS Clinical Trials Group A5212, a randomized, double-blind, placebo-controlled study, 99 HIV-infected patients on ART with plasma HIV-1 RNA levels ≤200 copies per milliliter for ≥6 months and CD4 lymphocyte counts <200 cells per cubic milliliter were randomized 1:1:1:1 to receive once daily intravenous administration of placebo or 20, 40, or 60 μg/kg of palifermin on 3 consecutive days.
RESULTS - The median change in the CD4 T-cell count from baseline to week 12 was not significantly different between the placebo arm [15 (-16, 23) cells/mm] and the 20-μg/kg dose [11 (2, 32) cells/mm], the 40-μg/kg dose [12 (-2, 25) cells/mm], or the 60-μg/kg dose arm [8 (-13, 35) cells/mm] of palifermin. No significant changes were observed in thymus size or in the number of naive T cells or recent thymic emigrants.
CONCLUSIONS - Palifermin in the doses studied was not effective in improving thymic function and did not raise CD4 lymphocyte counts in HIV-infected patients with low CD4 cell counts despite virologically effective ART.
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16 MeSH Terms
Both genome segments contribute to the pathogenicity of very virulent infectious bursal disease virus.
Escaffre O, Le Nouën C, Amelot M, Ambroggio X, Ogden KM, Guionie O, Toquin D, Müller H, Islam MR, Eterradossi N
(2013) J Virol 87: 2767-80
MeSH Terms: Amino Acid Sequence, Animals, Base Sequence, Birnaviridae Infections, Chick Embryo, Chickens, Infectious bursal disease virus, Molecular Dynamics Simulation, Poultry Diseases, Sequence Analysis, RNA, Spleen, Thymus Gland, Viral Structural Proteins
Show Abstract · Added April 26, 2017
Infectious bursal disease virus (IBDV) causes an economically significant disease of chickens worldwide. Very virulent IBDV (vvIBDV) strains have emerged and induce as much as 60% mortality. The molecular basis for vvIBDV pathogenicity is not understood, and the relative contributions of the two genome segments, A and B, to this phenomenon are not known. Isolate 94432 has been shown previously to be genetically related to vvIBDVs but exhibits atypical antigenicity and does not cause mortality. Here the full-length genome of 94432 was determined, and a reverse genetics system was established. The molecular clone was rescued and exhibited the same antigenicity and reduced pathogenicity as isolate 94432. Genetically modified viruses derived from 94432, whose vvIBDV consensus nucleotide sequence was restored in segment A and/or B, were produced, and their pathogenicity was assessed in specific-pathogen-free chickens. We found that a valine (position 321) that modifies the most exposed part of the capsid protein VP2 critically modified the antigenicity and partially reduced the pathogenicity of 94432. However, a threonine (position 276) located in the finger domain of the virus polymerase (VP1) contributed even more significantly to attenuation. This threonine is partially exposed in a hydrophobic groove on the VP1 surface, suggesting possible interactions between VP1 and another, as yet unidentified molecule at this amino acid position. The restored vvIBDV-like pathogenicity was associated with increased replication and lesions in the thymus and spleen. These results demonstrate that both genome segments influence vvIBDV pathogenicity and may provide new targets for the attenuation of vvIBDVs.
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13 MeSH Terms
Understanding velocardiofacial syndrome: how recent discoveries can help you improve your patient outcomes.
Chinnadurai S, Goudy S
(2012) Curr Opin Otolaryngol Head Neck Surg 20: 502-6
MeSH Terms: Animals, Branchial Region, Calcium, DiGeorge Syndrome, Genetic Therapy, Homeostasis, Humans, Parathyroid Glands, Phenotype, T-Box Domain Proteins, T-Lymphocytes, Thymus Gland, Tretinoin
Show Abstract · Added May 30, 2014
PURPOSE OF REVIEW - Improved recognition of velocardiofacial syndrome (VCFS) has led to increasing awareness of VCFS by otolaryngologists. Understanding the developmental biologic processes affected in VCFS patients will help improve treatment and outcomes. Advanced application of molecular labeling techniques has better outlined the role of T-Box transcription factor 1 (TBX1) as the primary genetic anomaly leading to VCFS. TBX1 plays multiple roles during branchial, cardiac, and craniofacial development and increased understanding of how these systems are affected by TBX1 mutations will improve patient outcomes. Furthermore, additional modifiers of TBX1 expression have been identified that may explain the variability of VCFS phenotypes. The phenotypic spectrum of VCFS may include cardiac anomalies, velopharyngeal insufficiency, aberrant calcium metabolism, and immune dysfunction. Recent interest has focused on the cognitive and neuropsychiatric manifestations of VCFS. Improved understanding of the biology of VCFS associated mutations has the potential to improve therapeutic outcomes.
RECENT FINDINGS - This article will discuss recent developmental biologic understanding of the role of TBX1 and genetic modifiers generating the phenotypic variability seen in VCFS patients. Special attention is given to advances in the realms of immunodeficiency, hypocalcemia, cardiac and arterial patterning anomalies, velopharyngeal insufficiency, as well as cognitive and psychiatric problems.
SUMMARY - Enhanced understanding of the multiple systems affected by TBX1 mutations will result in improved patient outcomes and improved family education. Future research will lead to improved detection of potential targets for gene therapy and change the way physicians counsel families and treat patients.
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13 MeSH Terms
IL-15 regulates homeostasis and terminal maturation of NKT cells.
Gordy LE, Bezbradica JS, Flyak AI, Spencer CT, Dunkle A, Sun J, Stanic AK, Boothby MR, He YW, Zhao Z, Van Kaer L, Joyce S
(2011) J Immunol 187: 6335-45
MeSH Terms: Animals, Cell Differentiation, Cell Lineage, Cell Survival, Homeostasis, Interleukin-15, Liver, Lymphocyte Count, Mice, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Natural Killer T-Cells, Spleen, Thymus Gland, bcl-X Protein
Show Abstract · Added December 10, 2013
Semi-invariant NKT cells are thymus-derived innate-like lymphocytes that modulate microbial and tumor immunity as well as autoimmune diseases. These immunoregulatory properties of NKT cells are acquired during their development. Much has been learned regarding the molecular and cellular cues that promote NKT cell development, yet how these cells are maintained in the thymus and the periphery and how they acquire functional competence are incompletely understood. We found that IL-15 induced several Bcl-2 family survival factors in thymic and splenic NKT cells in vitro. Yet, IL-15-mediated thymic and peripheral NKT cell survival critically depended on Bcl-x(L) expression. Additionally, IL-15 regulated thymic developmental stage 2 to stage 3 lineage progression and terminal NKT cell differentiation. Global gene expression analyses and validation revealed that IL-15 regulated Tbx21 (T-bet) expression in thymic NKT cells. The loss of IL-15 also resulted in poor expression of key effector molecules such as IFN-γ, granzyme A and C, as well as several NK cell receptors, which are also regulated by T-bet in NKT cells. Taken together, our findings reveal a critical role for IL-15 in NKT cell survival, which is mediated by Bcl-x(L), and effector differentiation, which is consistent with a role of T-bet in regulating terminal maturation.
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17 MeSH Terms
Inhibition of transplantation tolerance by immune senescence is reversed by endocrine modulation.
Zhao G, Moore DJ, Kim JI, Lee KM, O'Connor MR, Duff PE, Yang M, Lei J, Markmann JF, Deng S
(2011) Sci Transl Med 3: 87ra52
MeSH Terms: Aging, Animals, Antineoplastic Agents, Hormonal, Castration, Endocrine System, Gonads, Heart Transplantation, Humans, Immune System, Leukocyte Common Antigens, Leuprolide, Male, Mice, Mice, Inbred C3H, Mice, Inbred C57BL, Thymectomy, Thymus Gland, Transplantation Tolerance, Transplantation, Homologous
Show Abstract · Added October 24, 2013
The senescent immune system responds poorly to new stimuli; thymic involution, accumulation of memory cells against other specificities, and general refractoriness to antigen signaling all may contribute to poor resistance to infection. These same changes may pose a significant clinical barrier to organ transplantation, as transplantation tolerance requires thymic participation and integrated, tolerance-promoting responses to novel antigens. We found that after the age of 12 months, mice became resistant to the tolerance-inducing capacity of the monoclonal antibody therapy anti-CD45RB. This resistance to tolerance to cardiac allografts could be overcome by surgical castration of male mice, a procedure that led to thymic regeneration and long-term graft acceptance. The potential for clinical translation of this endocrine-immune interplay was confirmed by the ability of Lupron Depot injections, which temporarily disrupt gonadal function, to restore tolerance in aged mice. Furthermore, we demonstrated that the restoration of tolerance after surgical or chemical castration depended on thymic production of regulatory T cells (T(regs)); thymectomy or T(reg) depletion abrogated tolerance restoration. The aging of the immune system ("immune senescence") is a significant barrier to immune tolerance, but this barrier can be overcome by targeting sex steroid production with commonly used clinical therapeutics.
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19 MeSH Terms
Functional interaction between Foxd3 and Pax3 in cardiac neural crest development.
Nelms BL, Pfaltzgraff ER, Labosky PA
(2011) Genesis 49: 10-23
MeSH Terms: Animals, Craniofacial Abnormalities, Embryo Loss, Forkhead Transcription Factors, Mice, Mice, Mutant Strains, Neural Crest, PAX3 Transcription Factor, Paired Box Transcription Factors, Repressor Proteins, Sequence Deletion, Stem Cells, Thymus Gland, Truncus Arteriosus, Persistent
Show Abstract · Added March 31, 2011
The transcription factors Foxd3 and Pax3 are important early regulators of neural crest (NC) progenitor cell properties. Homozygous mutations of Pax3 or a homozygous NC-specific deletion of Foxd3 cause marked defects in most NC derivatives, but neither loss of both Foxd3 alleles nor loss of one Pax3 allele alone greatly affects overall development of cardiac NC derivatives. In contrast, compound mutant embryos homozygous for a NC-specific Foxd3 mutation and heterozygous for Pax3 have fully penetrant persistent truncus arteriosus, severe thymus hypoplasia, and midgestation lethality. Foxd3; Pax3 compound mutant embryos have increased cell death in the neural folds and a drastic early reduction of NC cells, with an almost complete absence of NC caudal to the first pharyngeal arch. The genetic interaction between these genes implicates gene dosage-sensitive roles for Foxd3 and Pax3 in cardiac NC progenitors. Foxd3 and Pax3 act together to affect survival and maintenance of cardiac NC progenitors, and loss of these progenitors catastrophically affects key aspects of later cardiovascular development.
Copyright © 2010 Wiley-Liss, Inc.
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14 MeSH Terms
SSBP2 is an in vivo tumor suppressor and regulator of LDB1 stability.
Wang Y, Klumpp S, Amin HM, Liang H, Li J, Estrov Z, Zweidler-McKay P, Brandt SJ, Agulnick A, Nagarajan L
(2010) Oncogene 29: 3044-53
MeSH Terms: Animals, Cell Differentiation, Cricetinae, DNA-Binding Proteins, Genes, Lethal, Genes, Tumor Suppressor, Humans, Mice, Mice, Inbred C57BL, Mice, Knockout, T-Lymphocytes, Thymus Gland, Transcription, Genetic, Tumor Suppressor Protein p53
Show Abstract · Added March 19, 2014
SSBP proteins bind and stabilize transcriptional cofactor LIM domain-binding protein1 (LDB1) from proteosomal degradation to promote tissue-specific transcription through an evolutionarily conserved pathway. The human SSBP2 gene was isolated as a candidate tumor suppressor from a critical region of loss in chromosome 5q14.1. By gene targeting, we show increased predisposition to B-cell lymphomas and carcinomas in Ssbp2(-/-) mice. Remarkably, loss of Ssbp2 causes increased LDB1 turnover in the thymus, a pathway exploited in Trp53(-/-)Ssbp2(-/-) mice to develop highly aggressive, immature thymic lymphomas. Using T-cell differentiation as a model, we report a stage-specific upregulation of Ssbp2 expression, which in turn regulates LDB1 turnover under physiological conditions. Furthermore, transcript levels of pTalpha, a target of LDB1-containing complex, and a critical regulator T-cell differentiation are reduced in Ssbp2(-/-) immature thymocytes. Our findings suggest that disruption of the SSBP2-regulated pathways may be an infrequent but critical step in malignant transformation of multiple tissues.
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14 MeSH Terms