bluuebunny/crossref_metadata_2025_split huggingface dataset:
IFN-γ Acts Directly on Activated CD4+ T Cells during Mycobacterial Infection to Promote Apoptosis by Inducing Components of the Intracellular Apoptosis Machinery and by Inducing Extracellular Proapoptotic Signals
Authors: Li Xujian , McKinstry K. Kai , Swain Susan L. , Dalton Dyana K. 
Published: April 2014

AbstractDespite many studies, the regulation of CD4+ T cell apoptosis during the shutdown of immune responses is not fully understood. We have investigated the molecular mechanisms of IFN-γ in regulating apoptosis of CD4+ T cells during bacillus Calmette-Guérin (BCG) infection of mice. Our data provide new insight into the regulation of CD4+ T cell apoptosis by IFN-γ. As CD4+ T cells responded to BCG infection, there was a coordinated increase in IFN-γ production by effector CD4+ T cells and a coordinated IFN-γ-dependent up-regulation of many diverse apoptosis-pathway genes in effector CD4+ T cells. Unexpectedly, IFN-γ up-regulated transcripts and protein expression of Bcl-2, Bax, Bim, Bid, Apaf-1, and caspase-9 in activated CD4+ T cells—components of the apoptosis machinery that are involved in promoting mitochondrial damage-mediated apoptosis. Wild-type, but not IFN-γ knockout, CD4+ T cells underwent apoptosis that was associated with damaged mitochondrial membranes. IFN-γ also up-regulated expression of cell-extrinsic signals of apoptosis, including TRAIL, DR5, and TNFR1. Cell-extrinsic apoptosis signals from TNF-α, TRAIL, and NO were capable of damaging the mitochondrial membranes in activated CD4+ T cells. Moreover, activated CD4+ T cells from BCG-infected DR5, TNFR1, and inducible NO synthase knockout mice had impaired caspase-9 activity, suggesting impaired mitochondria-pathway apoptosis. We propose that IFN-γ promotes apoptosis of CD4+ T cells during BCG infection as follows: 1) by sensitizing CD4+ T cells to apoptosis by inducing intracellular apoptosis molecules and 2) by inducing cell-extrinsic apoptosis signals that kill CD4+ effector T cells.
IL-2 Regulates Expansion of CD4+ T Cell Populations by Affecting Cell Death: Insights from Modeling CFSE Data
Authors: Ganusov Vitaly V. , Milutinović Dejan , De Boer Rob J. 
Published: April 2014

Abstract
It is generally accepted that IL-2 influences the dynamics of populations of T cells in vitro and in vivo. However, which parameters for cell division and/or death are affected by IL-2 is not well understood. To get better insights into the potential ways of how IL-2 may influence the population dynamics of T cells, we analyze data on the dynamics of CFSE-labeled polyclonal CD4+ T lymphocytes in vitro after anti-CD3 stimulation at different concentrations of exogenous IL-2. Inferring cell division and death rates from CFSE-delabeling experiments is not straightforward and requires the use of mathematical models. We find that to adequately describe the dynamics of T cells at low concentrations of exogenous IL-2, the death rate of divided cells has to increase with the number of divisions cells have undergone. IL-2 hardly affects the average interdivision time. At low IL-2 concentrations 1) fewer cells are recruited into the response and successfully complete their first division; 2) the stochasticity of cell division is increased; and 3) the rate, at which the death rate increases with the division number, increases. Summarizing, our mathematical reinterpretation suggests that the main effect of IL-2 on the in vitro dynamics of naive CD4+ T cells occurs by affecting the rate of cell death and not by changing the rate of cell division.
The Inflamed Central Nervous System Drives the Activation and Rapid Proliferation of Foxp3+ Regulatory T Cells
Authors: O’Connor Richard A. , Malpass Katy H. , Anderton Stephen M. 
Published: April 2014

Abstract
Resolution of experimental autoimmune encephalomyelitis requires a large cohort of Foxp3+ regulatory T cells (Tregs) within the CNS. In this study, we have used the passive transfer of murine experimental autoimmune encephalomyelitis using myelin-reactive T cells to study the development of this Treg response. Rapid proliferation of Tregs within the CNS (which is not seen in lymphoid organs) drives a switch in the balance of CNS proliferation from T effectors to Tregs, correlating with recovery. This proliferative burst drives a local over-representation of Vβ8+ Tregs in the CNS, indicative of an oligoclonal expansion. There is also evidence for a small, but detectable, myelin oligodendrocyte glycoprotein-reactive Treg component expanded without prior immunization. Furthermore, CNS-derived Tregs, taken during recovery, suppressed the proliferation of CNS-derived effectors in response to myelin oligodendrocyte glycoprotein. Under these conditions, Tregs could also limit the level of IFN-γ production, but not IL-17 production, by CNS-derived effectors. These data establish the CNS as an environment that permits extensive Treg proliferation and are the first to demonstrate Treg expansion specifically within the tissues during the natural resolution of autoimmune inflammation.
Induction of Regulatory T Cells and Dominant Tolerance by Dendritic Cells Incapable of Full Activation
Authors: Yates Stephen F. , Paterson Alison M. , Nolan Kathleen F. , Cobbold Stephen P. , Saunders Nigel J. , Waldmann Herman , Fairchild Paul J. 
Published: April 2014

Abstract
Transplants tolerated through a process known as infectious tolerance evoke continuous recruitment of regulatory T (Treg) cells that are necessary to maintain the unresponsive state. This state is maintained long-term and requires continuous Ag exposure. It is not known, however, whether infectious tolerance operates through sustained recruitment of pre-existing regulatory cells, induction of regulatory cells, or both. Using mice deficient in natural Treg cells, we show here that quiescent donor dendritic cells (DC) laden with histocompatibility Ag can induce Treg cells de novo that mediate transplantation tolerance. In contrast, fully activated DC fail to do so. These findings suggest that DC incapable of delivering full activation signals to naive T cells may favor their polarization toward a regulatory phenotype. Furthermore, they suggest a role for quiescent endogenous DC in the maintenance of the tolerant state.
Cross-Talk between Myeloid-Derived Suppressor Cells and Macrophages Subverts Tumor Immunity toward a Type 2 Response
Authors: Sinha Pratima , Clements Virginia K. , Bunt Stephanie K. , Albelda Steven M. , Ostrand-Rosenberg Suzanne 
Published: April 2014

Abstract
Although the immune system has the potential to protect against malignancies, many individuals with cancer are immunosuppressed. Myeloid-derived suppressor cells (MDSC) are elevated in many patients and animals with tumors, and contribute to immune suppression by blocking CD4+ and CD8+ T cell activation. Using the spontaneously metastatic 4T1 mouse mammary carcinoma, we now demonstrate that cross-talk between MDSC and macrophages further subverts tumor immunity by increasing MDSC production of IL-10, and by decreasing macrophage production of IL-12. Cross-talk between MDSC and macrophages requires cell-cell contact, and the IL-12 decrease is dependent on MDSC production of IL-10. Treatment with the chemotherapeutic drug gemcitabine, which reduces MDSC, promotes rejection of established metastatic disease in IL-4Rα−/− mice that produce M1 macrophages by allowing T cell activation, by maintaining macrophage production of IL-12, and by preventing increased production of IL-10. Therefore, MDSC impair tumor immunity by suppressing T cell activation and by interacting with macrophages to increase IL-10 and decrease IL-12 production, thereby promoting a tumor-promoting type 2 response, a process that can be partially reversed by gemcitabine.
IL-4 and IL-13 Negatively Regulate TNF-α- and IFN-γ-Induced β-Defensin Expression through STAT-6, Suppressor of Cytokine Signaling (SOCS)-1, and SOCS-3
Authors: Albanesi Cristina , Fairchild Heather R. , Madonna Stefania , Scarponi Claudia , De Pità Ornella , Leung Donald Y. M. , Howell Michael D. 
Published: April 2014

AbstractHuman β-defensins (HBDs) are a major class of antimicrobial peptides that play an important role in the innate immune response, however, the induction and regulation of these antimicrobial peptides is not well understood. We demonstrate here that stimulation of keratinocytes with TNF-α/IFN-γ induces HBD-2 and HBD-3 by activating STAT-1 and NF-κB signaling. We further demonstrate that IL-4 and IL-13 activate STAT-6 and induce the suppressors of cytokine signaling (SOCS)-1 and -3. This interferes with STAT-1 and NF-κB signaling, thereby inhibiting TNF-α/IFN-γ-mediated induction of HBD-2 and HBD-3. These data suggest that targeting the STAT-1-signaling pathway or suppressor of cytokine signaling expression enhances β-defensin expression and represents a new therapeutic strategy for reduction of infection in human diseases associated with β-defensin deficiency.
Deletional Self-Tolerance to a Melanocyte/Melanoma Antigen Derived from Tyrosinase Is Mediated by a Radio-Resistant Cell in Peripheral and Mesenteric Lymph Nodes
Authors: Nichols Lisa A. , Chen Yiming , Colella Teresa A. , Bennett Clare L. , Clausen Björn E. , Engelhard Victor H. 
Published: April 2014

AbstractSelf-tolerance to melanocyte differentiation Ags limits the ability to generate therapeutic antimelanoma responses. However, the mechanisms responsible for CD8 T cell tolerance to these Ags are unknown. We have used a newly generated TCR-transgenic mouse to establish the basis of tolerance to one such Ag from tyrosinase. Despite expression of tyrosinase transcripts in the thymus, central deletion does not shape the tyrosinase-specific CD8 T cell repertoire. We demonstrate that this endogenously expressed melanocyte Ag is constitutively presented in both peripheral and mesenteric lymph nodes, leading to abortive activation and deletion of tyrosinase-specific CD8 T cells. Importantly, this Ag is not presented by either radio-sensitive dendritic cells, or by radio-resistant Langerhans cells. Thus, for this endogenous Ag, cross-tolerization does not appear to be an operative mechanism. Instead, we find radioresistant tyrosinase mRNA expression in lymphoid compartments where CD8 T cell deletion occurs. This suggests that direct presentation of tyrosinase by radio-resistant lymph node resident cells is entirely responsible for tolerance to this endogenous melanocyte differentiation Ag.
Cutting Edge: Opposite Effects of IL-1 and IL-2 on the Regulation of IL-17+ T Cell Pool IL-1 Subverts IL-2-Mediated Suppression
Authors: Kryczek Ilona , Wei Shuang , Vatan Linhua , Escara-Wilke June , Szeliga Wojciech , Keller Evan T. , Zou Weiping 
Published: April 2014

Abstract
In this report, we show that IL-17+CD4+ and IL-17+CD8+ T cells are largely found in lung and digestive mucosa compartments in normal mice. Endogenous and exogenous IL-1 dramatically contribute to IL-17+ T cell differentiation mediated by TGFβ and IL-6. IL-1 is capable of stimulating IL-17+ T cell differentiation in the absence of IL-6. Furthermore, although IL-2 reduces IL-17+ T cell differentiation, IL-1 completely disables this effect. Mechanistically, IL-1 and IL-2 play opposite roles in regulating the expression of several molecules regulating Th17 cell differentiation, including the orphan nuclear receptor RORγt, the IL-1 receptor, and the IL-23 receptor. IL-1 subverts the effects of IL-2 on the expression of these gene transcripts. Altogether, our work demonstrates that IL-6 is important but not indispensable for IL-17+ T cell differentiation and that IL-1plays a predominant role in promoting IL-17+ T cell induction. Thus, the IL-17+ T cell pool may be controlled by the local cytokine profile in the microenvironment.
TNF-α Drives Human CD14+ Monocytes to Differentiate into CD70+ Dendritic Cells Evoking Th1 and Th17 Responses
Authors: Iwamoto Sanju , Iwai Shin-ichi , Tsujiyama Kazuko , Kurahashi Chika , Takeshita Kumiko , Naoe Michio , Masunaga Atsuko , Ogawa Yoshio , Oguchi Katsuji , Miyazaki Akira 
Published: April 2014

AbstractMany mechanisms involving TNF-α, Th1 responses, and Th17 responses are implicated in chronic inflammatory autoimmune disease. Recently, the clinical impact of anti-TNF therapy on disease progression has resulted in re-evaluation of the central role of this cytokine and engendered novel concept of TNF-dependent immunity. However, the overall relationship of TNF-α to pathogenesis is unclear. Here, we demonstrate a TNF-dependent differentiation pathway of dendritic cells (DC) evoking Th1 and Th17 responses. CD14+ monocytes cultured in the presence of TNF-α and GM-CSF converted to CD14+ CD1alow adherent cells with little capacity to stimulate T cells. On stimulation by LPS, however, they produced high levels of TNF-α, matrix metalloproteinase (MMP)-9, and IL-23 and differentiated either into mature DC or activated macrophages (Mφ). The mature DC (CD83+ CD70+ HLA-DR high CD14low) expressed high levels of mRNA for IL-6, IL-15, and IL-23, induced naive CD4 T cells to produce IFN-γ and TNF-α, and stimulated resting CD4 T cells to secret IL-17. Intriguingly, TNF-α added to the monocyte culture medium determined the magnitude of LPS-induced maturation and the functions of the derived DC. In contrast, the Mφ (CD14highCD70+CD83−HLA-DR−) produced large amounts of MMP-9 and TNF-α without exogenous TNF stimulation. These results suggest that the TNF priming of monocytes controls Th1 and Th17 responses induced by mature DC, but not inflammation induced by activated Mφ. Therefore, additional stimulation of monocytes with TNF-α may facilitate TNF-dependent adaptive immunity together with GM-CSF-stimulated Mφ-mediated innate immunity.
Xenogeneic β2-Microglobulin Substitution Alters NK Cell Function
Authors: Benoît Loralyn A. , Tan Rusung 
Published: April 2014

Abstract
Recently, it has been shown that human β2-microglobulin (h-β2m) blocks the association between the NK cell inhibitory receptor Ly49C and H-2Kb. Given this finding, we therefore sought to assess the immunobiology of NK cells derived from C57BL/6 (H-2b) mice expressing exclusively h-β2m. Initial analysis revealed that the Ly49C expression profile of NK cells from h-β2m+ mice was modified, despite the fact that H-2Kb expression was normal in these mice. Moreover, the NK cells were not anergic in that IL-2 treatment of h-β2m+ NK cells in vitro enabled efficient lysis of prototypic tumor cell lines as well as of syngeneic h-β2m+ lymphoblasts. This loss of self-tolerance appeared to correlate with the activation status of h-β2m+ NK cells because quiescent h-β2m+ transplant recipients maintained h-β2m+ grafts but polyinosine:polycytidylic acid-treated recipients acutely rejected h-β2m+ grafts. NK cell reactivity toward h-β2m+ targets was attributed to defective Ly49C interactions with h-β2m:H-2Kb molecules. With regard to NK cell regulatory mechanisms, we observed that h-β2m:H-2Kb complexes in the cis-configuration were inefficient at regulating Ly49C and, furthermore, that receptor-mediated uptake of h-β2m:H-2Kb by Ly49C was impaired compared with uptake of mouse β2m:H-2Kb. Thus, we conclude that transgenic expression of h-β2m alters self-MHC class I in such a way that it modulates the NK cell phenotype and interferes with regulatory mechanisms, which in turn causes in vitro-expanded and polyinosine:polycytidylic acid-activated NK cells to be partially self-reactive similar to what is seen with NK cells derived from MHC class I-deficient mice.
Molecular and Functional Characterization of IL-15 in Rainbow TroutOncorhynchus mykiss:A Potent Inducer of IFN-γ Expression in Spleen Leukocytes
Authors: Wang Tiehui , Holland Jason W. , Carrington Allison , Zou Jun , Secombes Christopher J. 
Published: April 2014

AbstractIL-15 is a member of the common γ-chain family of cytokines that possess a heterogeneous repertoire of activities on various cells of the immune system. We report here the first functional characterization of a fish IL-15 in rainbow trout. The trout IL-15 gene is 6-kb long and contains six exons and five introns that transcribe into a 1.2-kb mRNA containing seven out-of-frame AUG initiation codons and translate into a 193-aa peptide. Potential sites for transcriptional activators and repressors have been identified in the trout IL-15 gene. Like IL-15 from other species, trout IL-15 is closely linked to an INPP4B gene, but there is also a BCL10 gene located between the IL-15 and INPP4B genes. Three alternative splicing variants of the trout IL-15 gene have also been identified and their expression in vivo was studied. Trout IL-15 expression is present in all the tissues and cell lines studied. Recombinant trout IFN-γ selectively increased IL-15 expression but had little effect on other cytokines such as IL-1β and IL-11. Recombinant trout IL-15 preferentially stimulated splenic leukocytes from healthy fish, where it induced a large increase in IFN-γ expression, with little, if any, effect on IL-1β expression. This effect was quite long-lived, and was still apparent 24 h poststimulation. Although the exact cell types being affected have still to be determined, it is clear that once produced IL-15 will have a profound affect on the ability of the fish immune system to activate antimicrobial defenses and genes induced themselves by IFN-γ.
CD8+ Dendritic Cells Use LFA-1 to Capture MHC-Peptide Complexes from Exosomes In Vivo
Authors: Segura Elodie , Guérin Coralie , Hogg Nancy , Amigorena Sebastian , Théry Clotilde 
Published: April 2014

Abstract
Exosomes are secreted vesicles formed in late endocytic compartments. Mature dendritic cells (DCs) secrete exosomes bearing functional MHC-peptide complexes and high levels of ICAM-1. Such exosomes can activate Ag-specific naive T cells but only after recapture by recipient APCs. In this study, we addressed the molecular mechanisms of interaction between exosomes and recipient DCs. We show that exosomes can be presented by mouse DCs without the need for internalization and processing. Exosomes interact with DCs through a specific saturable receptor. Although the two major ligands of ICAM-1, LFA-1 and Mac-1, are expressed by lymphoid organ DCs, only LFA-1 is required for exosome capture by these cells. Accordingly, we show that CD8+ DCs express higher levels of LFA-1 than CD8− DCs, and that they are the main recipients of exosomes in vivo. We propose a new role for LFA-1 on DCs, as a receptor for exosomes to favor Ag transfer between DCs in vivo.
CD86 Regulates IgG1 Production via a CD19-Dependent Mechanism
Authors: Kin Nicholas W. , Sanders Virginia M. 
Published: April 2014

Abstract
CD86 signals directly in a B cell to activate PI3K and increase the rate of IgG1 production, without affecting germline transcription. However, the mechanism by which CD86 activates PI3K in a B cell and the relevance of CD86 stimulation in vivo remains unknown. We show that the addition of CD28/Ig to CD40 ligand/IL-4-activated wild-type, but not CD86- or CD19-deficient, B cells increased the level of phosphorylation for Lyn and CD19, as well as the amount of Lyn, Vav, and PI3K that immunoprecipitated with CD19. Adoptive transfer of CD86-deficient B cells and wild-type CD4+ T cells into RAG2-deficient mice and immunization with trinitrophenylated keyhole limpet hemocyanin resulted in an IL-4 and germline IgG1 response equivalent to control mice, but a decrease in serum IgG1. Thus, our findings suggest that CD86 plays a key role in regulating the level of IgG1 produced in vitro and in vivo, and that Lyn and CD19 may be the signaling intermediates activated by CD86 proximal to PI3K.
Spontaneous and Prostatic Steroid Binding Protein Peptide-Induced Autoimmune Prostatitis in the Nonobese Diabetic Mouse
Authors: Penna Giuseppe , Amuchastegui Susana , Cossetti Chiara , Aquilano Francesca , Mariani Roberto , Giarratana Nadia , De Carli Elena , Fibbi Benedetta , Adorini Luciano 
Published: April 2014

Abstract
Chronic nonbacterial prostatitis is a poorly defined syndrome of putative autoimmune origin. To further understand its pathogenesis, we have analyzed autoimmune prostatitis in the NOD mouse, a strain genetically prone to develop different organ-specific autoimmune diseases. Spontaneous development of autoimmune prostatitis in the NOD male, defined by lymphomonuclear cell infiltration in the prostate gland, is well-established by ∼20 wk of age and is stably maintained afterward. Disease development is indistinguishable in NOD and NOR mice, but is markedly delayed in IFN-γ-deficient NOD mice. A T cell response to the prostate-specific autoantigen prostatic steroid-binding protein (PSBP) can be detected in NOD males before development of prostate infiltration, indicating lack of tolerance to this self Ag. The intraprostatic inflammatory infiltrate is characterized by Th1-type CD4+ T cells, which are able to transfer autoimmune prostatitis into NOD.SCID recipients. We characterize here experimental autoimmune prostatitis, detected by intraprostatic infiltrate and PSBP-specific T cell responses, induced in 6- to 8-wk-old NOD males by immunization with synthetic peptides corresponding to the C1 subunit of PSBP. Three PSBP peptides induce in NOD mice vigorous T and B cell responses, paralleled by a marked lymphomononuclear cell infiltration in the prostate. Two of these peptides, PSBP21–40 and PSBP61–80, correspond to immunodominant self epitopes naturally processed in NOD mice after immunization with PSBP, whereas peptide PSBP91–111 represents a cryptic epitope. These model systems address pathogenetic mechanisms in autoimmune prostatitis and will facilitate testing and mechanistic analysis of therapeutic approaches in this condition.
Sphingosine 1-Phosphate-Mediated Trafficking of Pathogenic Th2 and Mast Cells for the Control of Food Allergy
Authors: Kurashima Yosuke , Kunisawa Jun , Higuchi Morio , Gohda Masashi , Ishikawa Izumi , Takayama Naoko , Shimizu Miki , Kiyono Hiroshi 
Published: April 2014

Abstract
Sphingosine 1-phosphate (S1P) has been proposed as a regulator of lymphocyte trafficking, but its role in mucosa-associated diseases, such as in food allergies, remains to be elucidated. To examine the role of S1P in allergic diseases in the intestine, we used a Th2 cell-mediated Ag-specific allergic diarrhea model and demonstrated that type 1 S1P receptor (S1P1) expression was preferentially associated with pathogenic CD4+ T cells for the development of allergic reactions. Consistent with this demonstration, treatment with FTY720, a modulator of the S1P1, prevented allergic diarrhea by inhibiting the migration of systemically primed pathogenic CD4+ T cells induced by oral challenge with allergen into the large intestine. In addition, FTY720 hampered mast cell infiltration into the large intestine, whereas eosinophil infiltration into the large intestine and total and allergen-specific serum IgE production were comparable between mock- and FTY720-treated groups. These results suggest that modulation of the S1P-mediated pathway to inhibit the migration of pathogenic CD4+ T cells and mast cells into the large intestine could be a novel strategy for preventing allergic diarrhea.