bluuebunny/crossref_metadata_2025_split huggingface dataset:
Thymic Emigration: When and How T Cells Leave Home
Authors: Weinreich Michael A. , Hogquist Kristin A. 
Published: April 2014

AbstractThe thymus supports the differentiation of multiple distinct T cell subsets that play unique roles in the immune system. CD4 and CD8 α/β T cells, γ/δ T cells, NKT cells, regulatory T cells, and intraepithelial lymphocytes all develop in the thymus and must leave it to provide their functions elsewhere in the body. This article will review recent research indicating differences in the time and migration patterns of T cell subsets found in the thymus. Additionally, we review current understanding of the molecules involved in thymocyte emigration, including the sphingolipid receptor S1P1 and its regulation by the Krüppel-like transcription factor KLF2.
Rapid NKT Cell Responses Are Self-Terminating during the Course of Microbial Infection
Authors: Chiba Asako , Dascher Christopher C. , Besra Gurdal S. , Brenner Michael B. 
Published: April 2014

Abstract
NKT cells play a protective role in immune responses against infectious pathogens. However, when the NKT cell response to infection is initiated and terminated is unknown. In this study, we demonstrate that NKT cells become activated, proliferate, and exert their effector function before MHC-restricted T cells during infection with Mycobacterium bovis bacillus Calmette-Guérin in mice. After a cell expansion phase, NKT cells underwent cell death, which contracts their numbers back to baseline. Surprisingly, despite ongoing infection, the remaining NKT cells were profoundly unresponsive to TCR stimulation, while MHC-restricted T cells were vigorously proliferating and producing IFN-γ. Similarly, we show that NKT cells became unresponsive in uninfected mice after receiving a single exposure to a TLR agonist LPS, suggesting that NKT cell unresponsiveness may be a major mechanism of terminating their response in many infectious conditions. This characterization of the NKT cell response in antimicrobial immunity indicates that rapid NKT cell activation contributes to the innate phase of the response to the infectious pathogen, but then, the NKT cell response is shut down by two mechanisms; apoptotic contraction and marked unresponsiveness to TCR stimulation, as a synchronized hand off to MHC-restricted T cells occurs.
Differential Requirement for the SAP-Fyn Interaction during NK T Cell Development and Function
Authors: Nunez-Cruz Selene , Yeo W. C. Janice , Rothman Jennifer , Ojha Priti , Bassiri Hamid , Juntilla Marisa , Davidson Dominique , Veillette André , Koretzky Gary A. , Nichols Kim E. 
Published: April 2014

Abstract
The adaptor molecule SAP (signaling lymphocytic activation molecule-associated protein) plays a critical role during NK T (NKT) cell development in humans and mice. In CD4+ T cells, SAP interacts with the tyrosine kinase Fyn to deliver signals required for TCR-induced Th2-type cytokine production. To determine whether the SAP-dependent signals controlling NKT cell ontogeny rely on its binding to Fyn, we used the OP9-DL1 system to initiate structure function studies of SAP in murine NKT cell development. In cultures containing wild-type (WT) hematopoietic progenitors, we noted the transient emergence of cells that reacted with the NKT cell-specific agonist α-galactosyl ceramide and its analog PBS57. Sap−/− cells failed to give rise to NKT cells in vitro; however, their development could be rescued by re-expression of WT SAP. Emergence of NKT cells was also restored by a mutant version of SAP (SAP R78A) that cannot bind to Fyn, but with less efficiency than WT SAP. This finding was accentuated in vivo in SapR78A knock-in mice as well as SapR78A competitive bone marrow chimeras, which retained NKT cells but at significantly reduced numbers compared with controls. Unlike SapR78A CD4+ T cells, which produce reduced levels of IL-4 following TCR ligation, α-galactosyl ceramide-stimulated NKT cells from the livers and spleens of SapR78A mice produced Th2 cytokines and activated NK cells in a manner mimicking WT cells. Thus, SAP appears to use differential signaling mechanisms in NKT cells, with optimal ontogeny requiring Fyn binding, while functional responses occur independently of this interaction.
Immunosuppressive Effect of Isopropanol: Down-Regulation of Cytokine Production Results from the Alteration of Discrete Transcriptional Pathways in Activated Lymphocytes
Authors: Désy Olivier , Carignan Damien , Caruso Manuel , de Campos-Lima Pedro O. 
Published: April 2014

Abstract
Isopropanol (IPA) is widely used in household applications and constitutes a leading cause of acute alcohol intoxication second only to ethanol. Although the effects of ethanol on the immune system have been extensively studied, far fewer data are available on IPA. Given the structural similarity between the two molecules, we hypothesized that IPA could as well have immunomodulatory properties. We report here that acute IPA exposure is detrimental to human T lymphocyte and NK cell activity in vitro in concentrations as low as 0.08–0.16% (13–26 mM). IPA treatment did not affect receptor-mediated early signaling but had a reproducible and dose-dependent effect on the nuclear translocation of NFAT and AP-1. Furthermore, we show in a model of acute IPA intoxication that animals became immunosuppressed as judged by their reduced ability to release IL-2 and IFN-γ in the serum in response to staphylococcal enterotoxin B. This effect was also associated to the down-regulation of TNF-α production and was sufficiently strong to rescue susceptible animals from enterotoxin-induced toxic shock. Our results suggest that IPA is potentially immunosuppressive to the adaptive and innate immune system and have broad significance given the exposure of the general population to this ubiquitous chemical.
Functional Characterization and Gene Expression Analysis of CD4+CD25+ Regulatory T Cells Generated in Mice Treated with 2,3,7,8-Tetrachlorodibenzo-p-Dioxin
Authors: Marshall Nikki B. , Vorachek William R. , Steppan Linda B. , Mourich Dan V. , Kerkvliet Nancy I. 
Published: April 2014

Abstract
Although the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are mediated through binding and activation of the aryl hydrocarbon receptor (AhR), the subsequent biochemical and molecular changes that confer immune suppression are not well understood. Mice exposed to TCDD during an acute B6-into-B6D2F1 graft-vs-host response do not develop disease, and recently this has been shown to correlate with the generation of CD4+ T cells that express CD25 and demonstrate in vitro suppressive function. The purpose of this study was to further characterize these CD4+ cells (TCDD-CD4+ cells) by comparing and contrasting them with both natural regulatory CD4+ T cells (T-regs) and vehicle-treated cells. Cellular anergy, suppressive functions, and cytokine production were examined. We found that TCDD-CD4+ cells actively proliferate in response to various stimuli but suppress IL-2 production and the proliferation of effector T cells. Like natural T-regs, TCDD-CD4+ cells do not produce IL-2 and their suppressive function is contact dependent but abrogated by costimulation through glucocorticoid-induced TNFR (GITR). TCDD-CD4+ cells also secrete significant amounts of IL-10 in response to both polyclonal and alloantigen stimuli. Several genes were significantly up-regulated in TCDD-CD4+ cells including TGF-β3, Blimp-1, and granzyme B, as well as genes associated with the IL12-Rb2 signaling pathway. TCDD-CD4+ cells demonstrated an increased responsiveness to IL-12 as indicated by the phosphorylation levels of STAT4. Only 2% of TCDD-CD4+ cells express Foxp3, suggesting that the AhR does not rely on Foxp3 for suppressive activity. The generation of CD4+ cells with regulatory function mediated through activation of the AhR by TCDD may represent a novel pathway for the induction of T-regs.
Activation of γδ T Cells by Borrelia burgdorferi Is Indirect via a TLR- and Caspase-Dependent Pathway
Authors: Collins Cheryl , Shi Cuixia , Russell Jennifer Q. , Fortner Karen A. , Budd Ralph C. 
Published: April 2014

Abstract
Activation of the innate immune system typically precedes engagement of adaptive immunity. Cells at the interface between these two arms of the immune response are thus critical to provide full engagement of host defense. Among the innate T cells at this interface are γδ T cells. γδ T cells contribute to the defense from a variety of infectious organisms, yet little is understood regarding how they are activated. We have previously observed that human γδ T cells of the Vδ1 subset accumulate in inflamed joints in Lyme arthritis and proliferate in response to stimulation with the causative spirochete, Borrelia burgdorferi. We now observe that murine γδ T cells are also activated by B. burgdorferi and that in both cases the activation is indirect via TLR stimulation on dendritic cells or monocytes. Furthermore, B. burgdorferi stimulation of monocytes via TLR, and secondary activation of γδ T cells, are both caspase-dependent.
Homeostatic Proliferation in the Mice with Germline FoxP3 Mutation and its Contribution to Fatal Autoimmunity
Authors: Chang Xing , Zheng Pan , Liu Yang 
Published: April 2014

Abstract
FoxP3 has emerged as a critical regulator for the development and function of regulatory T cells. Recent studies by several groups have demonstrated that FoxP3 is expressed outside T cell lineages. In this context, we have reported that germline mutation of FoxP3 caused defective thymopoiesis, although its potential contribution to autoimmune diseases has not been analyzed. In this study, we report that, during perinatal period, germline mutation of FoxP3 in scurfy mice caused lymphopenia in the spleen and massive homeostatic proliferation, characterized by the independence from cognate Ags and expression of bona fide markers for homeostatic proliferation. The homeostatic proliferation is suppressed by increases in T cell numbers but not by adoptive transfer of regulatory T cells (Treg). Adoptive transfer of Treg-containing bulk T cells was dramatically more effective than transfer of either Treg alone or Treg-depleted CD4 T cells in curing the scurfy mice. Our data demonstrated that FoxP3 mutation not only ablates Treg, but also dramatically increased homeostatic proliferation during the perinatal period. Homeostatic proliferation acts in concert with Treg defects in causing acute and fatal autoimmune diseases in the FoxP3 mutant mice. These results demonstrated that germline mutation of FoxP3 caused two defects that work in concert to cause lethal autoimmunity.
Colonization with Heligmosomoides polygyrus Suppresses Mucosal IL-17 Production
Authors: Elliott David E. , Metwali Ahmed , Leung John , Setiawan Tommy , Blum Arthur M. , Ince M. Nedim , Bazzone Lindsey E. , Stadecker Miguel J. , Urban Joseph F. , Weinstock Joel V. 
Published: April 2014

Abstract
Helminth exposure appears to protect hosts from inappropriate inflammatory responses, such as those causing inflammatory bowel disease. A recently identified, strongly proinflammatory limb of the immune response is characterized by T cell IL-17 production. Many autoimmune type inflammatory diseases are associated with IL-17 release. Because helminths protect from these diseases, we examined IL-17 production in helminth-colonized mice. We colonized mice with Heligmosomoides polygyrus, an intestinal helminth, and analyzed IL-17 production by lamina propria mononuclear cells (LPMC) and mesenteric lymph node (MLN) cells. Colonization with H. polygyrus reduces IL-17A mRNA by MLN cells and inhibits IL-17 production by cultured LPMC and MLN cells. Helminth exposure augments IL-4 and IL-10 production. Blocking both IL-4 and IL-10, but not IL-10 alone, restores IL-17 production in vitro. Colonization of colitic IL-10-deficient mice with H. polygyrus suppresses LPMC IL-17 production and improves colitis. Ab-mediated blockade of IL-17 improves colitis in IL-10-deficient mice. Thus, helminth-associated inhibition of IL-17 production is most likely an important mechanism mediating protection from inappropriate intestinal inflammation.
CD11c+CD11b+ Dendritic Cells Play an Important Role in Intravenous Tolerance and the Suppression of Experimental Autoimmune Encephalomyelitis
Authors: Li Hongmei , Zhang Guang-Xian , Chen Youhai , Xu Hui , Fitzgerald Denise C. , Zhao Zhao , Rostami Abdolmohamad 
Published: April 2014

Abstract
The central role of T cells in the induction of immunological tolerance against i.v. Ags has been well documented. However, the role of dendritic cells (DCs), the most potent APCs, in this process is not clear. In the present study, we addressed this issue by examining the involvement of two different DC subsets, CD11c+CD11b+ and CD11c+CD8+ DCs, in the induction of i.v. tolerance. We found that mice injected i.v. with an autoantigen peptide of myelin oligodendrocyte glycoprotein (MOG) developed less severe experimental autoimmune encephalomyelitis (EAE) following immunization with MOG peptide but presented with more CD11c+CD11b+ DCs in the CNS and spleen. Upon coculturing with T cells or LPS, these DCs exhibited immunoregulatory characteristics, including increased production of IL-10 and TGF-β but reduced IL-12 and NO; they were also capable of inhibiting the proliferation of MOG-specific T cells and enhancing the generation of Th2 cells and CD4+CD25+Foxp3+ regulatory T cells. Furthermore, these DCs significantly suppressed ongoing EAE upon adoptive transfer. These results indicate that CD11c+CD11b+ DCs, which are abundant in the CNS of tolerized animals, play a crucial role in i.v. tolerance and EAE and may be a candidate cell population for immunotherapy of autoimmune diseases.
CD46-Induced Immunomodulatory CD4+ T Cells Express the Adhesion Molecule and Chemokine Receptor Pattern of Intestinal T Cells
Authors: Alford Shannon K. , Longmore Gregory D. , Stenson William F. , Kemper Claudia 
Published: April 2014

Abstract
Tissue homing of activated T cells is typically mediated through their specific integrin and chemokine receptor repertoire. Activation of human primary CD4+ T cells in the presence of CD46 cross-linking induces the development of a distinct immunomodulatory T cell population characterized by high IL-10/granzyme B production. How these regulatory T cells (Tregs) migrate/home to specific tissue sites is not understood. In this study, we determined the adhesion protein and chemokine receptor expression pattern on human CD3/CD46-activated peripheral blood CD4+ T cells. CD3/CD46-activated, but not CD3/CD28-activated, T cells up-regulate the integrin α4β7. The interaction of α4β7 with its ligand mucosal addressin cell adhesion molecule 1 (MAdCAM-1) mediates homing or retention of T cells to the intestine. CD3/CD46-activated Tregs adhere to/roll on MAdCAM-1-expressing HeLa cells, similar to T cells isolated from the human lamina propria (LP). This interaction is inhibited by silencing MAdCAM-1 expression in HeLa cells or by the addition of blocking Abs to β7. CD46 activation of T cells also induced the expression of the surface-bound cytokine LIGHT and the chemokine receptor CCR9, both marker constitutively expressed by gut LP-resident T cells. In addition, we found that ∼10% of the CD4+ T lymphocytes isolated from the LP of patients undergoing bariatric surgery contain T cells that spontaneously secrete a cytokine pattern consistent with that from CD46-activated T cells. These data suggest that CD46-induced Tregs might play a role in intestinal immune homeostasis where they could dampen unwanted effector T cell responses through local IL-10/granzyme B production.
Terminal Deoxynucleotidyltransferase Is Required for the Establishment of Private Virus-Specific CD8+ TCR Repertoires and Facilitates Optimal CTL Responses
Authors: Kedzierska Katherine , Thomas Paul G. , Venturi Vanessa , Davenport Miles P. , Doherty Peter C. , Turner Stephen J. , La Gruta Nicole L. 
Published: April 2014

Abstract
Virus-immune CD8+ TCR repertoires specific for particular peptide-MHC class I complexes may be substantially shared between (public), or unique to, individuals (private). Because public TCRs can show reduced TdT-mediated N-region additions, we analyzed how TdT shapes the heavily public (to DbNP366) and essentially private (to DbPA224) CTL repertoires generated following influenza A virus infection of C57BL/6 (B6, H2b) mice. The DbNP366-specific CTL response was virtually clonal in TdT−/− B6 animals, with one of the three public clonotypes prominent in the wild-type (wt) response consistently dominating the TdT−/− set. Furthermore, this massive narrowing of TCR selection for DbNP366 reduced the magnitude of DbNP366-specific CTL response in the virus-infected lung. Conversely, the DbPA224-specific responses remained comparable in both magnitude and TCR diversity within individual TdT−/− and wt mice. However, the extent of TCR diversity across the total population was significantly reduced, with the consequence that the normally private wt DbPA224-specific repertoire was now substantially public across the TdT−/− mouse population. The key finding is thus that the role of TdT in ensuring enhanced diversity and the selection of private TCR repertoires promotes optimal CD8+ T cell immunity, both within individuals and across the species as a whole.
Stable CD8+ T Cell Memory during Persistent Trypanosoma cruzi Infection
Authors: Bixby Lisa M. , Tarleton Rick L. 
Published: April 2014

Abstract
CD8+ T cell responses to persistent infections caused by intracellular pathogens are dominated by resting T effectors and T effector memory cells, with little evidence suggesting that a T central memory (TCM) population is generated. Using a model of Trypanosoma cruzi infection, we demonstrate that in contrast to the T effector/T effector memory phenotype of the majority of T. cruzi-specific CD8+ T cells, a population of cells displaying hallmark characteristics of TCM cells is also present during long-term persistent infection. This population expressed the TCM marker CD127 and a subset expressed one or more of three other TCM markers: CD62L, CCR7, and CD122. Additionally, the majority of CD127high cells were KLRG1low, indicating that they have not been repetitively activated through TCR stimulation. These CD127high cells were better maintained than their CD127low counterparts following transfer into naive mice, consistent with their observed surface expression of CD127 and CD122, which confer the ability to self-renew in response to IL-7 and IL-15. CD127high cells were capable of IFN-γ production upon peptide restimulation and expanded in response to challenge infection, indicating that these cells are functionally responsive upon Ag re-encounter. These results are in contrast to what is typically observed during many persistent infections and indicate that a stable population of parasite-specific CD8+ T cells capable of Ag-independent survival is maintained in mice despite the presence of persistent Ag.
NF-κB Activation Controls Phagolysosome Fusion-Mediated Killing of Mycobacteria by Macrophages
Authors: Gutierrez Maximiliano Gabriel , Mishra Bibhuti B. , Jordao Luisa , Elliott Edith , Anes Elsa , Griffiths Gareth 
Published: April 2014

Abstract
Macrophages can potentially kill all mycobacteria by poorly understood mechanisms. In this study, we explore the role of NF-κB in the innate immune response of macrophages against Mycobacterium smegmatis, a nonpathogenic mycobacterium efficiently killed by macrophages, and Mycobacterium avium which survives within macrophages. We show that infection of macrophages with M. smegmatis induces an activation of NF-κB that is essential for maturation of mycobacterial phagosomes and bacterial killing. In contrast, the pathogenic M. avium partially represses NF-κB activation. Using microarray analysis, we identified many lysosomal enzymes and membrane-trafficking regulators, including cathepsins, LAMP-2 and Rab34, were regulated by NF-κB during infection. Our results argue that NF-κB activation increases the synthesis of membrane trafficking molecules, which may be rate limiting for regulating phagolysosome fusion during infection. The direct consequence of NF-κB inhibition is the impaired delivery of lysosomal enzymes to M. smegmatis phagosomes and reduced killing. Thus, the established role of NF-κB in the innate immune response can now be expanded to include regulation of membrane trafficking during infection.
Ly-6G+CCR2− Myeloid Cells Rather Than Ly-6ChighCCR2+ Monocytes Are Required for the Control of Bacterial Infection in the Central Nervous System
Authors: Mildner Alexander , Djukic Marija , Garbe David , Wellmer Andreas , Kuziel William A. , Mack Matthias , Nau Roland , Prinz Marco 
Published: April 2014

Abstract
Myeloid cell recruitment is a characteristic feature of bacterial meningitis. However, the cellular mechanisms important for the control of Streptococcus pneumoniae infection remain largely undefined. Previous pharmacological or genetic studies broadly depleted many myeloid cell types within the meninges, which did not allow defining the function of specific myeloid subsets. Herein we show that besides CD11b+Ly-6G+CCR2− granulocytes, also CD11b+Ly-6ChighCCR2+ but not Ly-6ClowCCR2− monocytes were recruited in high numbers to the brain as early as 12 h after bacterial challenge. Surprisingly, CD11b+Ly-6ChighCCR2+ inflammatory monocytes modulated local CXCL2 and IL-1β production within the meninges but did not provide protection against bacterial infection. Consistent with these results, CCR2 deficiency strongly impaired monocyte recruitment to the infected brains but was redundant for disease pathogenesis. In contrast, specific depletion of polymorphonuclear granulocytes caused elevated local bacterial titer within the brains, led to an aggravated clinical course, and enhanced mortality. These findings demonstrate that Ly-6ChighCCR2+ inflammatory monocytes play a redundant role for the host defense during bacterial meningitis and that predominantly CD11b+Ly-6G+CCR2− myeloid cells are involved in the restriction of the extracellular bacteria.
TLR Expression on Neutrophils at the Pulmonary Site of Infection: TLR1/TLR2-Mediated Up-Regulation of TLR5 Expression in Cystic Fibrosis Lung Disease
Authors: Koller Barbara , Kappler Matthias , Latzin Phillip , Gaggar Amit , Schreiner Marcus , Takyar Sherkin , Kormann Michael , Kabesch Michael , Roos Dirk , Griese Matthias , Hartl Dominik 
Published: April 2014

Abstract
Cystic fibrosis (CF) lung disease is characterized by infection with Pseudomonas aeruginosa and a sustained accumulation of neutrophils. In this study, we analyzed 1) the expression of MyD88-dependent TLRs on circulating and airway neutrophils in P. aeruginosa-infected CF patients, P. aeruginosa-infected non-CF bronchiectasis patients, and noninfected healthy control subjects and 2) studied the regulation of TLR expression and functionality on neutrophils in vitro. TLR2, TLR4, TLR5, and TLR9 expression was increased on airway neutrophils compared with circulating neutrophils in CF and bronchiectasis patients. On airway neutrophils, TLR5 was the only TLR that was significantly higher expressed in CF patients compared with bronchiectasis patients and healthy controls. Studies using confocal microscopy and flow cytometry revealed that TLR5 was stored intracellularly in neutrophils and was mobilized to the cell surface in a protein synthesis-independent manner through protein kinase C activation or after stimulation with TLR ligands and cytokines characteristic of the CF airway microenvironment. The most potent stimulator of TLR5 expression was the bacterial lipoprotein Pam3CSK4. Ab-blocking experiments revealed that the effect of Pam3CSK4 was mediated through cooperation of TLR1 and TLR2 signaling. TLR5 activation enhanced the phagocytic capacity and the respiratory burst activity of neutrophils, which was mediated, at least partially, via a stimulation of IL-8 production and CXCR1 signaling. This study demonstrates a novel mechanism of TLR regulation in neutrophils and suggests a critical role for TLR5 in neutrophil-P. aeruginosa interactions in CF lung disease.