bluuebunny/crossref_metadata_2025_split huggingface dataset:
Thyrocytes Responding to IFN-γ Are Essential for Development of Lymphocytic Spontaneous Autoimmune Thyroiditis and Inhibition of Thyrocyte Hyperplasia
Authors: Yu Shiguang , Sharp Gordon C. , Braley-Mullen Helen 
Published: April 2014

Abstract
IFN-γ promotes the development of lymphocytic spontaneous autoimmune thyroiditis (L-SAT) in NOD.H-2h4 mice and inhibits the development of thyrocyte hyperplasia and proliferation (TEC H/P). The precise mechanisms by which IFN-γ promotes L-SAT and inhibits TEC H/P are unknown. To determine whether responsiveness of lymphocytes or thyrocytes to IFN-γ is important for the development of these lesions, IFN-γR−/− mice, which develop TEC H/P similar to IFN-γ−/− mice, were used as recipients for adoptive cell transfer. Wild-type (WT) splenocytes or bone marrow induced L-SAT and inhibited TEC H/P in IFN-γ−/−, but not IFN-γR−/− recipients. IFN-γR−/− recipients of WT cells developed severe TEC H/P, but did not develop L-SAT, suggesting that thyrocytes responding to IFN-γ are important for inhibition of TEC H/P. Unexpectedly, IFN-γR−/− splenocytes or bone marrow did not induce L-SAT in IFN-γ−/− or WT mice even though IFN-γR−/− lymphocyte donors produced as much IFN-γ as lymphocytes from WT donors, and thyrocytes could respond to IFN-γ. Real-time PCR indicated that recipients of IFN-γR−/− bone marrow expressed less mRNA for IFN-γ-inducible chemokines compared with recipients of WT bone marrow. This might limit the migration of IFN-γR−/− lymphocytes to thyroids. Few IFN-γR−/− lymphocytes infiltrated thyroids even in the presence of WT lymphocytes, suggesting that lymphocytes unable to respond to IFN-γ are not induced to migrate to thyroids. These results suggest that thyrocytes must be able to respond to IFN-γ for the development of L-SAT and inhibition of TEC H/P, and lymphocytes must be able to respond to IFN-γ to induce L-SAT.
Ex Vivo-Expanded CD4+CD25+ Immunoregulatory T Cells Prevent Graft-versus-Host-Disease by Inhibiting Activation/Differentiation of Pathogenic T Cells
Authors: Trenado Aurélie , Sudres Muriel , Tang Qizhi , Maury Sébastien , Charlotte Frédéric , Grégoire Sylvie , Bonyhadi Mark , Klatzmann David , Salomon Benoît L. , Cohen José L. 
Published: April 2014

Abstract
CD4+CD25+ immunoregulatory T cells (Tregs) can be administered to inhibit graft-vs-host disease (GVHD) while preserving graft-vs-leukemia activity after allogeneic bone marrow transplantation in mice. Preclinical studies suggest that it is necessary to infuse as many Tregs as conventional donor T cells to achieve a clinical effect on GVHD. Thus, it would be necessary to expand Tregs ex vivo before transplantation. Two strategies have been proposed: expansion of Tregs stimulated by anti-CD3/CD28-coated microbeads for polyclonal activation or by host-type allogeneic APCs for selecting Tregs specific for host Ags. In this study, we describe the mechanisms by which ex vivo-expanded Tregs act on donor T cells to prevent GVHD in mice. We demonstrate that expanded Tregs strongly inhibited the division, expansion, and differentiation of donor T cells, with a more pronounced effect with Tregs specific for host Ags. These latter cells permit the efficient and durable control of GVHD and favor immune reconstitution.
HIV-Specific IL-10-Positive CD8+ T Cells Are Increased in Advanced Disease and Are Associated with Decreased HIV-Specific Cytolysis
Authors: Elrefaei Mohamed , Barugahare Banson , Ssali Francis , Mugyenyi Peter , Cao Huyen 
Published: April 2014

Abstract
IL-10-producing T cells have been shown to inhibit Ag-specific CD8+ T cell responses, and may play a role in the immune dysregulation observed in HIV-1 infection. We characterized the Gag-specific IL-10 responses by CD8+ T cells in HIV-1-positive volunteers from Uganda. HIV-specific IL-10 responses were detected in 32 of 61 (52.4%) antiretroviral naive and 2 of 15 (13.3%) volunteers with a complete virologic response on antiretroviral therapy (&lt; 400 copies/ml). The frequency of HIV-specific IL-10-positive cells was significantly higher in volunteers with advanced disease (CD4+ T cell count &lt;200 cells/mm3; p = 0.0004), and correlated positively with plasma HIV RNA (r = 0.43, p = 0.0004). Interestingly, the frequency of Gag-specific CD107a/b-, but not IFN-γ-, positive cells was significantly lower in individuals with detectable IL-10-positive CD8+ T cells (p = 0.004). Gag-specific IL-10-positive CD8+ T cells demonstrated a pattern of surface memory marker expression that is distinct compared with CD107a/b- and IFN-γ-positive CD8+ T cell populations (p &lt; 0.0001). Our study describes a distinct population of IL-10-positive CD8+ T cells that may play a role in HIV-associated immune dysfunction.
A Case for Regulatory B Cells
Authors: Mizoguchi Atsushi , Bhan Atul K. 
Published: April 2014

Abstract
B cells are typically characterized by their ability to produce Abs, including autoantibodies. However, B cells possess additional immune functions, including the production of cytokines and the ability to function as a secondary APC. As with T cells, the B cell population contains functionally distinct subsets capable of performing both pathogenic and regulatory functions. Recent studies indicate that regulatory B cells develop in several murine models of chronic inflammation, including inflammatory bowel disease, rheumatoid arthritis, and experimental autoimmune encephalomyelitis. The regulatory function may be directly accomplished by the production of regulatory cytokines IL-10 and TGF-β and/or by the ability of B cells to interact with pathogenic T cells to dampen harmful immune responses. In this review, we make a case for the existence of regulatory B cells and discuss the possible developmental pathways and functional mechanisms of these B cells.
Cutting Edge: Evidence for Ligand-Independent Multimerization of the IL-17 Receptor
Authors: Kramer Jill M. , Yi Ling , Shen Fang , Maitra Amarnath , Jiao Xuanmao , Jin Tian , Gaffen Sarah L. 
Published: April 2014

AbstractIL-17 and its receptor are founding members of a novel inflammatory cytokine family. To date, only one IL-17 receptor subunit has been identified, termed IL-17RA. All known cytokine receptors consist of a complex of multiple subunits. Although IL-17-family cytokines exist as homodimers, the configuration and stoichiometry of the IL-17R complex remain unknown. We used fluorescence resonance energy transfer (FRET) to determine whether IL-17RA subunits multimerize, and, if so, whether they are preassembled in the plasma membrane. HEK293 cells coexpressing IL-17RA fused to cyan or yellow fluorescent proteins (CFP or YFP) were used to evaluate FRET before and after IL-17A or IL-17F treatment. In the absence of ligand, IL-17RA molecules exhibited significant specific FRET efficiency, demonstrating that they exist in a multimeric, preformed receptor complex. Strikingly, treatment with IL-17A or IL-17F markedly reduced FRET efficiency, suggesting that IL-17RA subunits within the IL-17R complex undergo a conformational change upon ligand binding.
Cutting Edge: Modulation of Fas-Mediated Apoptosis by Lipid Rafts in T Lymphocytes
Authors: Legembre Patrick , Daburon Sophie , Moreau Patrick , Moreau Jean-François , Taupin Jean-Luc 
Published: April 2014

Abstract
In type I cells, Fas-mediated cell death requires cytoplasmic membrane subdomains called microdomains or lipid rafts. On the contrary, Fas signaling is independent of these structures in type II cells. We report that in human T cells, CD28, CD59, and CD55 are all localized into lipid rafts and that CD28 is concentrated into microdomains enriched in ganglioside GM1, whereas CD59 and CD55 are not. Moreover, CD28 cross-linking leads to the formation of lipid raft clusters which exclude CD59 and CD55, and reciprocally. Coligation of Fas with CD55 or CD59 inhibits the apoptotic signal, whereas CD28 recruitment amplifies the Fas signaling pathway. Therefore, we conclude that 1) different types of microdomains exist on the cell surface, with distinct functional properties and 2) the recruitment of these distinct structures may differentially modulate the Fas pathway. Moreover, our results demonstrate that Fas-induced apoptosis can be controlled at the level of the cytoplasmic membrane.
Cutting Edge: Tissue Inhibitor of Metalloproteinase 3 Regulates TNF-Dependent Systemic Inflammation
Authors: Smookler David S. , Mohammed Fazilat F. , Kassiri Zamaneh , Duncan Gordon S. , Mak Tak W. , Khokha Rama 
Published: April 2014

Abstract
Host response to infectious agents must be rapid and powerful. One mechanism is the release of presynthesized membrane-bound TNF. TNF shedding is mediated by TNF-α converting enzyme, which is selectively inhibited by the tissue inhibitor of metalloproteinase 3 (TIMP3). We show that loss of TIMP3 impacts innate immunity by dysregulating cleavage of TNF and its receptors. Cultured timp3−/− macrophages release more TNF in response to LPS than wild-type macrophages. In timp3−/− mice, LPS causes serum levels of TNF and its receptors to rise more rapidly and remain higher compared with wild-type mice. The altered kinetics of ligand and receptor shedding enhances TNF signaling in timp3−/− mice, indicated by elevated serum IL-6. Physiologically, timp3−/− mice are more susceptible to LPS-induced mortality. Ablation of the TNF receptor gene p55 (Tnfrsf1a) or treatment with a synthetic metalloproteinase inhibitor rescues timp3−/− mice. Thus, TIMP3 is essential for normal innate immune function.
Cutting Edge: Heligmosomoides polygyrus Induces TLR4 on Murine Mucosal T Cells That Produce TGFβ after Lipopolysaccharide Stimulation
Authors: Ince M. Nedim , Elliott David E. , Setiawan Tommy , Blum Arthur , Metwali Ahmed , Wang Ying , Urban Joseph F. , Weinstock Joel V. 
Published: April 2014

Abstract
Helminths are immune modulators that down-regulate colitis in inflammatory bowel disease. In animal models, intestinal bacteria drive colitis and in humans certain alleles of the LPS receptor protein TLR4 increase inflammatory bowel disease susceptibility. To understand helminthic immune modulation in the gut, we studied the influence of intestinal Heligmosomoides polygyrus colonization on LPS-induced lamina propria mononuclear cell (LPMC) cytokine responses in mice. LPS did not stimulate TGFβ production from LPMC of uninfected mice. LPS strongly induced LPMC from worm-infected animals to secrete TGFβ, but not TNF-α or IL-12. The TGFβ derived from mucosal T cells. Helminth infection up-regulated TLR4 expression only in lamina propria T cells. LPMC from worm-infected TLR4 mutant animals did not respond to LPS, suggesting that LPS required TLR4 to stimulate TGFβ secretion. Thus, during helminth infection, LPS challenge induces mucosal T cells to make TGFβ through a TLR4-dependent process without promoting synthesis of proinflammatory cytokines.
Cutting Edge: Three-Dimensional Architecture of the Thymus Is Required to Maintain Delta-Like Expression Necessary for Inducing T Cell Development
Authors: Mohtashami Mahmood , Zúñiga-Pflücker Juan Carlos 
Published: April 2014

Abstract
The three-dimensional microarchitecture of the thymus plays a unique role in directing T cell lineage commitment and development. This is supported by the fact that, in contrast to fetal thymic organ cultures, thymic stromal cell monolayer cultures (TSMC) fail to support T lymphopoiesis. Nevertheless, OP9-DL1 cell monolayer cultures induce T lineage commitment and differentiation. Thus, the inability of TSMC to support T lymphopoiesis may be due to a loss of Notch ligand expression and/or function during culture. In this study, we report that, in contrast to fetal thymic organ cultures, TSMC fail to maintain expression of the Notch ligands, Delta-like (Dll) 1 and Dll4, and concomitantly lose the ability to support T lymphopoiesis. Importantly, ectopic re-expression of Dll1 or Dll4 is sufficient to restore the ability of TSMC to support T lymphopoiesis. These findings demonstrate that maintenance of endogenous Dll1 or Dll4 expression by thymic stromal cells is required for the commitment and differentiation of T cells in the absence of a three-dimensional microenvironment.
Cutting Edge: Innate Immune Cells Contribute to the IFN-γ-Dependent Regulation of Antigen-Specific CD8+ T Cell Homeostasis
Authors: Sercan Özen , Hämmerling Günter J. , Arnold Bernd , Schüler Thomas 
Published: April 2014

Abstract
IFN-γ has a dual function in the regulation of T cell homeostasis. It promotes the expansion of effector T cells and simultaneously programs their contraction. The cellular mechanisms leading to this functional dichotomy of IFN-γ have not been identified to date. In this study we show: 1) that expansion of wild-type CD8+ T cells is defective in IFN-γ-deficient mice but increased in IFN-γR-deficient mice; and 2) that contraction of the effector CD8+ T cell pool is impaired in both mouse strains. Furthermore, we show that CD11b+ cells responding to IFN-γ are sufficient to limit CD8+ T cell expansion and promote contraction. The data presented here reveal that IFN-γ directly promotes CD8+ T cell expansion and simultaneously induces suppressive functions in CD11b+ cells that counter-regulate CD8+ T cell expansion, promote contraction, and limit memory formation. Thus, innate immune cells contribute to the IFN-γ-dependent regulation of Ag-specific CD8+ T cell homeostasis.
T Cell Zones of Lymphoid Organs Constitutively Express Th1 Cytokine mRNA: Specific Changes during the Early Phase of an Immune Response
Authors: Kalies Kathrin , Blessenohl Maike , Nietsch Julia , Westermann Jürgen 
Published: April 2014

Abstract
The cytokine milieu of the T cell zones in lymphoid organs is involved in the activation of naive T cells. Quantitative data regarding the local expression of cytokines are lacking. Therefore, the expression of Th1 (IL-2, IL-12p40, IFN-γ), Th2 (IL-4, IL-10), as well as TGFβ1 and IL-15 mRNA was studied after laser microdissection in the steady state and during an immune response in rats. Our results show that Th1 cytokines are preferentially found in lymphoid tissues and in the T cell zones, whereas Th2 cytokines are expressed throughout the organs and especially in the B cell zones. After injection of sheep RBC, IL-2 and IFN-γ mRNA are significantly increased in the T cell zone only, a change not seen by analyzing the whole spleen. Studying the spatial and temporal expression of genes will reveal new insights into the regulation of immune responses.
Human Monocytes as Intermediaries between Allogeneic Endothelial Cells and Allospecific T Cells: A Role for Direct Scavenger Receptor-Mediated Endothelial Membrane Uptake in the Initiation of Alloimmunity
Authors: Xu He , Dhanireddy Kiran K. , Kirk Allan D. 
Published: April 2014

Abstract
Recipient monocytes, T cells, and donor endothelial cells (ECs) are recognized as critical components of allograft rejection. We have recently shown that human monocytes infiltrate vascularized allografts before clinical rejection and have thus hypothesized that monocytes, rather than costimulation-poor ECs, initiate an alloimmune response. However, the nature of the interactions between ECs, monocytes, and T cells has been incompletely defined. Specifically, it is not clear whether these cells interact in a hierarchical manner, nor is it apparent what constitutes an interaction. We therefore studied human ECs, monocytes, and T cells in various isolated in vitro combinations to define the salient features of their contact and to determine whether their interactions were sequential in nature. We find that T cells proliferate poorly to allogeneic ECs and autologous monocytes but well to autologous monocytes following allogeneic EC contact. We show that monocytes gain their stimulatory capacity by phagocytizing allogeneic but not autologous EC membranes in a process governed by scavenger receptors. This process facilitates the subsequent presentation of intact donor HLA molecules to T cells (semidirect presentation). Moreover, monocytes are receptive to T cell help only after exposure to ECs and require CD4+ T cells to optimally express costimulatory molecules and foster Ag presentation. Our results indicate that monocytes engage allogeneic ECs through scavenger receptors and are then primed to facilitate T cell activation in a codependent manner. This reciprocal codependence allows for monocytes to serve as a regulated bridge between the allograft and T cells.
Role of Breast Milk in a Mouse Model of Maternal Transmission of Asthma Susceptibility
Authors: Leme Adriana S. , Hubeau Cedric , Xiang Yuhong , Goldman Alejandra , Hamada Kaoru , Suzaki Yasue , Kobzik Lester 
Published: April 2014

Abstract
Epidemiologic data suggest a link between nursing by asthmatic mothers and increased risk of allergy in babies. We sought to experimentally test the potential contribution of breast milk mediator(s) in a mouse model of maternal transmission of asthma risk by evaluating the effect of adoptive nursing on asthma susceptibility in the offspring. We measured airway hyperresponsiveness (AHR) and allergic airway inflammation (AI) after an intentionally suboptimal OVA Ag sensitization, tested the allergen independence of the maternal effect by using a second allergen, casein, for sensitization of the baby mice, and tested the potential role of cytokines by measuring their levels in breast milk. Offspring of asthmatic, but not normal, mothers showed AHR and AI, indicating a maternal transfer of asthma risk. After adoptive nursing, both groups (litters born to asthmatic mothers and nursed by normal mothers, and normal babies nursed by asthmatic mothers) showed AHR (enhanced pause after methacholine aerosol, 50 mg/ml, 3.7 ± 0.7, 4.2 ± 0.5, respectively, vs 1.1 ± 0.1 normal controls, n = 25, p &lt; 0.01) and AI, seen as eosinophilia on histology and bronchoalveolar lavage (40.7 ± 4.5%, 28.7 ± 3.7%, vs 1.0 ± 0.5% normals, n = 25, p &lt; 0.01) after OVA sensitization. Similar results using casein allergen were observed. Multiplex assays for cytokines (IFN-γ, IL-2, IL-4, IL-5, TNF-α, and IL-13) in breast milk were negative. Breast milk is sufficient, but not necessary, to mediate allergen-independent maternal transmission of asthma risk to offspring.
Lymphoid Sequestration of Alloreactive Memory CD4 T Cells Promotes Cardiac Allograft Survival
Authors: Zhang Qiwei , Chen Yifa , Fairchild Robert L. , Heeger Peter S. , Valujskikh Anna 
Published: April 2014

Abstract
Memory T cells specific for donor Ags present a unique challenge in transplantation. In addition to expressing robust immune responses to a transplanted organ, memory T cells may be resistant to the effects of immunosuppressive therapies used to prolong graft survival. In this study, we explore the possibility of controlling deleterious donor-reactive memory CD4 T cells through lymphoid sequestration. We showed that sphingosine 1-phosphate receptor-1 agonist FTY720 induces relocation of circulating memory CD4 T cells into secondary lymphoid organs. Lymphoid sequestration of these donor-reactive memory CD4 T cells prolonged survival of murine heterotopic cardiac allografts and synergizes with conventional costimulatory blockade to further increase graft survival. Despite limited trafficking, memory CD4 T cells remain capable of providing help for the induction of anti-donor CD8 T cell and alloantibody responses. Elimination of antidonor humoral immunity resulted in indefinite allograft survival proving the pathogenicity of alloantibody under these conditions. Overall, this is the first demonstration that FTY720 influences memory CD4 T cell trafficking and attenuates their contribution to allograft rejection. The data have important implications for guiding FTY720 therapy and for designing combinatorial strategies aimed at prolonging allograft survival in sensitized transplant patients with donor-specific memory T cells.
Galectin-3 and Galectin-1 Bind Distinct Cell Surface Glycoprotein Receptors to Induce T Cell Death
Authors: Stillman Brianna N. , Hsu Daniel K. , Pang Mabel , Brewer C. Fred , Johnson Pauline , Liu Fu-Tong , Baum Linda G. 
Published: April 2014

AbstractGalectins are a family of mammalian β-galactoside-binding proteins that positively and negatively regulate T cell death. Extracellular galectin-1 directly induces death of T cells and thymocytes, while intracellular galectin-3 blocks T cell death. In contrast to the antiapoptotic function of intracellular galectin-3, we demonstrate that extracellular galectin-3 directly induces death of human thymocytes and T cells. However, events in galectin-3- and galectin-1-induced cell death differ in a number of ways. Thymocyte subsets demonstrate different susceptibility to the two galectins: whereas galectin-1 kills double-negative and double-positive human thymocytes with equal efficiency, galectin-3 preferentially kills double-negative thymocytes. Galectin-3 binds to a complement of T cell surface glycoprotein receptors distinct from that recognized by galectin-1. Of these glycoprotein receptors, CD45 and CD71, but not CD29 and CD43, appear to be involved in galectin-3-induced T cell death. In addition, CD7 that is required for galectin-1-induced death is not required for death triggered by galectin-3. Following galectin-3 binding, CD45 remains uniformly distributed on the cell surface, in contrast to the CD45 clustering induced by galectin-1. Thus, extracellular galectin-3 and galectin-1 induce death of T cells through distinct cell surface events. However, as galectin-3 and galectin-1 cell death are neither additive nor synergistic, the two death pathways may converge inside the cell.
Early Preplasma Cells Define a Tolerance Checkpoint for Autoreactive B Cells
Authors: Culton Donna A. , O’Conner Brian P. , Conway Kara L. , Diz Ramiro , Rutan Jennifer , Vilen Barbara J. , Clarke Stephen H. 
Published: April 2014

Abstract
Ab-secreting plasma cells (PCs) are the effectors of humoral immunity. In this study, we describe regulation of autoreactive B cells specific for the ribonucleoprotein Smith (Sm) at an early pre-PC stage. These cells are defined by the expression of the PC marker CD138 and normal levels of CD19 and B220. They are present at a high frequency in normal mouse spleen and bone marrow, are Ag dependent, and are located predominantly along the T cell-B cell border and near bridging channels. Anti-Sm pre-PCs also occur at a high frequency in nonautoimmune mice and show additional phenotypic characteristics of PC differentiation. However, while some of these pre-PCs are Ab-secreting cells, those specific for Sm are not, indicating regulation. Consistent with this, anti-Sm pre-PCs have a higher turnover rate and higher frequency of cell death than those that do not bind Sm. Regulation of anti-Sm pre-PCs occurs upstream of the transcriptional repressor, B lymphocyte-induced maturation protein-1, expression. Regulation at this stage is overcome in autoimmune MRL/lpr mice and is accompanied by an altered B lymphocyte stimulator receptor profile. These data reveal a new B cell tolerance checkpoint that is overcome in autoimmunity.