bluuebunny/crossref_metadata_2025_split huggingface dataset:
Breaking of CD8+ T Cell Tolerance through In Vivo Ligation of CD40 Results in Inhibition of Chronic Graft-versus-Host Disease and Complete Donor Cell Engraftment
Authors: Kim Juyang , Park Keunhee , Kim Hyun J. , Kim Jiyoung , Kim Hyun-A , Jung Daehee , Kim Hye J. , Choi Hye-Jeong , Choi Suck-Young , Seo Kwang W. , Cho Hong R. , Kwon Byungsuk 
Published: April 2014

AbstractIn the DBA/2 → unirradiated (C57BL/6 × DBA/2)F1 model of chronic graft-vs-host disease (cGVHD), donor CD4+ T cells play a critical role in breaking host B cell tolerance, while donor CD8+ T cells are rapidly removed and the remaining cells fall into anergy. Previously we have demonstrated that in vivo ligation of GITR (glucocorticoid-induced TNF receptor-related gene) can activate donor CD8+ T cells, subsequently converting the disease pattern from cGVHD to an acute form. In this study, we investigated the effect of an agonistic mAb against CD40 on cGVHD. Treatment of anti-CD40 mAb inhibited the production of anti-DNA IgG1 autoantibody and the development of glomerulonephritis. The inhibition of cGVHD occurred because anti-CD40 mAb prevented donor CD8+ T cell anergy such that subsequently activated donor CD8+ T cells deleted host CD4+ T cells and host B cells involved in autoantibody production. Additionally, functionally activated donor CD8+ T cells induced full engraftment of donor hematopoietic cells and exhibited an increased graft-vs-leukemia effect. However, induction of acute GVHD by donor CD8+ T cells seemed to be not so apparent. Further CTL analysis indicated that there were lower levels of donor CTL activity against host cells in mice that received anti-CD40 mAb, compared with mice that received anti-GITR mAb. Taken together, our results suggest that a different intensity of donor CTL activity is required for removal of host hematopoietic cells, including leukemia vs induction of acute GVHD.
Telomerase-Based Pharmacologic Enhancement of Antiviral Function of Human CD8+ T Lymphocytes
Authors: Fauce Steven Russell , Jamieson Beth D. , Chin Allison C. , Mitsuyasu Ronald T. , Parish Stan T. , Ng Hwee L. , Ramirez Kitchen Christina M. , Yang Otto O. , Harley Calvin B. , Effros Rita B. 
Published: April 2014

Abstract
Telomerase reverse transcribes telomere DNA onto the ends of linear chromosomes and retards cellular aging. In contrast to most normal somatic cells, which show little or no telomerase activity, immune cells up-regulate telomerase in concert with activation. Nevertheless, during aging and chronic HIV-1 infection, there are high proportions of dysfunctional CD8+ CTL with short telomeres, suggesting that telomerase is limiting. The present study shows that exposure of CD8+ T lymphocytes from HIV-infected human donors to a small molecule telomerase activator (TAT2) modestly retards telomere shortening, increases proliferative potential, and, importantly, enhances cytokine/chemokine production and antiviral activity. The enhanced antiviral effects were abrogated in the presence of a potent and specific telomerase inhibitor, suggesting that TAT2 acts primarily through telomerase activation. Our study is the first to use a pharmacological telomerase-based approach to enhance immune function, thus directly addressing the telomere loss immunopathologic facet of chronic viral infection.
Uncoupling of Induced Protein Processing from Maturation in Dendritic Cells Exposed to a Highly Antigenic Preparation from a Helminth Parasite
Authors: Marshall Fraser A. , Pearce Edward J. 
Published: April 2014

AbstractTLR ligands induce dendritic cell (DC) maturation. During this process, cells initiate proteolytic degradation of internalized protein Ags into peptides that complex with MHC class II (MHC II) and simultaneously increase expression of costimulatory molecules and of cytokines such as IL-6, IL-12, and IL-23. In these ways, TLR-activated DCs are able to activate naive Th cells and initiate Th1 and Th17 responses, and TLR ligands thus serve as adjuvants for these types of responses. In contrast, products from helminth parasites generally do not activate DCs and act as adjuvants for Th2 response induction. We have explored the underlying basis for this form of adjuvanticity. We show that exposure of DCs to soluble Ags from the eggs of the helminth parasite Schistosoma mansoni (schistosome egg Ag (SEA)) leads to the induction of proteolysis of internalized Ag. This occurs in the absence of significant induction of costimulatory molecule expression or production of proinflammatory cytokines. SEA-induced Ag processing occurs independently of MyD88 or Toll/IL-1 receptor domain containing adaptor inducing IFN-β (Trif), but is significantly attenuated by inhibition of p38, but not ERK, signaling. In DCs exposed to SEA, ligation of CD40 provides a necessary second signal that stimulates costimulatory molecule expression, allowing DCs to mature into capable APCs. Collectively, the data demonstrate the existence of a MyD88/Trif-independent, p38-dependent pathway of Ag processing in DCs, which is uncoupled from conventional DC maturation and is associated with induction of Th2-type immune responses.
Protective Immunity to Systemic Infection with AttenuatedSalmonella entericaserovar Enteritidis in the Absence of IL-12 Is Associated with IL-23-Dependent IL-22, but Not IL-17
Authors: Schulz Silke M. , Köhler Gabriele , Schütze Nicole , Knauer Jens , Straubinger Reinhard K. , Chackerian Alissa A. , Witte Ellen , Wolk Kerstin , Sabat Robert , Iwakura Yoichiro , Holscher Christoph , Müller Uwe , Kastelein Robert A. , Alber Gottfried 
Published: April 2014

AbstractIL-12 is essential for protective T cell-mediated immunity against Salmonella infection. To characterize the role of the related cytokine IL-23, wild-type (WT) C57BL/6 and p19−/− mice were infected systemically with an attenuated strain of Salmonella enterica serovar Enteritidis (S. Enteritidis). IL-23-deficient mice controlled infection with S. Enteritidis similarly as WT mice. Similar IFN-γ production as compared with WT mice, but defective IL-17A and IL-22 production was found in the absence of IL-23. Nevertheless, although IL-23 is required for T cell-dependent cytokine responses, IL-23 is dispensable for protection against S. Enteritidis when IL-12 is present. To analyze the role of IL-23 in the absence of IL-12, low doses of S. Enteritidis were administered to p35−/− mice (lacking IL-12), p35/19−/− mice (lacking IL-12 and IL-23), p35/40−/− mice (lacking IL-12, IL-23, and homodimeric IL-12p40), or p35/IL-17A−/− mice (lacking IL-12 and IL-17A). We found survival of p35−/− and p35/IL-17A−/− mice, whereas p35/19−/− and p35/40−/− mice died within 3–6 wk and developed liver necrosis. This indicates that IL-23, but not homodimeric IL-12p40, is required for protection, which, surprisingly, is independent of IL-17A. Moreover, protection was associated with IL-22, but not IL-17F or IL-21 expression or with neutrophil recruitment. Finally, anti-IL-22 treatment of S. Enteritidis-infected p35−/− mice resulted in liver necrosis, indicating a central role of IL-22 in hepatocyte protection during salmonellosis. In conclusion, IL-23-dependent IL-22, but not IL-17 production is associated with protection against systemic infection with S. Enteritidis in the absence of IL-12.
SOCS1 Regulates the IFN but Not NFκB Pathway in TLR-Stimulated Human Monocytes and Macrophages
Authors: Prêle Cecilia M. , Woodward Eleanor A. , Bisley Jacqueline , Keith-Magee April , Nicholson Sandra E. , Hart Prue H. 
Published: April 2014

AbstractSOCS1 can regulate TLR-mediated signal transduction, yet mechanistic studies in murine macrophages have been confusing and contradictory. This study has used an adenoviral transfection system to determine the role of SOCS1 in the regulation of TNF-α production by activated human monocytes. Monocytes were infected with AdV-SOCS1 or with an empty vector control, AdV-GFP, for 24 h before activation with the TLR4 ligand, LPS. SOCS1 did not regulate TNF-α mRNA or protein production within the first two hours of TLR4 activation. However, SOCS1 suppressed the sustained production of TNF-α by primary human monocytes and synovial fluid macrophages ex vivo. In addition, SOCS1 regulated the production of IL-6, but not IL-10, by monocytes. Analysis of the early signaling pathway downstream of TLR4 demonstrated that SOCS1 had no regulatory effect on the activation or on the DNA binding capacity of NFκB. The late effects of LPS are mediated in part through the MyD88-independent pathway activating IRF3 and initiating the production of IFN-β. In response to adenoviral infection and before LPS exposure, monocytes expressed enhanced levels of IFN-β and Myxovirus A mRNA, an anti-viral molecule characterizing IFN-β activity. These two genes were reduced in AdV-SOCS1-infected cells. Further, SOCS1 regulated IFN-dependent pathways in LPS-activated cells as evidenced by reduced IFN-β production and STAT1 phosphorylation. Using AdV-infection to dissect SOCS1 control of IFN-dependent pathways, this study suggests that SOCS1-regulation of the IFN-dependent component of the LPS-induced TLR4 signaling pathway may contribute to the down-regulation of inflammatory cytokine production by AdV-SOCS1-infected human monocytes.
Sulfatide, A Major Lipid Component of Myelin Sheath, Activates Inflammatory Responses As an Endogenous Stimulator in Brain-Resident Immune Cells
Authors: Jeon Sae-Bom , Yoon Hee Jung , Park Se-Ho , Kim In-Hoo , Park Eun Jung 
Published: April 2014

Abstract
Sulfatide, a major lipid component of myelin sheath, participates in diverse cellular events of the CNS, and its cellular level has recently been implicated in many inflammation-associated neuronal diseases. Herein, we report that sulfatide alone can trigger pathological inflammatory responses in glia, brain-resident immune cells. We show that sulfatide changed the morphology of primary microglia to their activated form, and it significantly induced the production of various inflammatory mediators in primary microglia and astrocytes. Moreover, sulfatide rapidly triggered the phosphorylation of p38, ERK, and JNK within 30 min, and it markedly enhanced the NF binding activity to NF-κB and AP-1 binding elements. However, nonsulfated galactocerebroside, another major lipid component of myelin, had no effect on activation of glia. We further reveal that CD1d did not contribute to sulfatide-stimulated activation of MAPKs, although its expression was enhanced by sulfatide and sulfatide-treated microglial cells actually stimulated type II NKT cells. Sulfatide significantly stimulated the phosphorylation of MAPKs in glia from CD1d-deficient mice, and the phosphorylation levels were similar to those in wild-type littermates. Sulfatide-triggered inflammatory events appear to occur at least in part through an L-selectin-dependent mechanism. L-selectin was dramatically down-regulated upon exposure to sulfatide, and inhibition of L-selectin resulted in suppression of sulfatide-triggered responses. Collectively, these results show that abnormally released sulfatide at demyelinated regions may act as an endogenous stimulator in the brain immune system, thus causing and further exacerbating pathological conditions in the brain.
Intrarectal Vaccination with Recombinant Vaccinia Virus Expressing Carcinoembronic Antigen Induces Mucosal and Systemic Immunity and Prevents Progression of Colorectal Cancer
Authors: Kim-Schulze Seunghee , Kim Hong Sung , Wainstein Alberto , Kim Dae Won , Yang Wein Cui , Moroziewicz Dorota , Mong Phyllus Y. , Bereta Michal , Taback Bret , Wang Qin , Kaufman Howard L. 
Published: April 2014

Abstract
The gastrointestinal mucosa contains an intact immune system that protects the host from pathogens and communicates with the systemic immune system. Absorptive epithelial cells in the mucosa give rise to malignant tumors although the interaction between tumor cells and the mucosal immune system is not well defined. The pathophysiology of colorectal cancer has been elucidated through studies of hereditary syndromes, such as familial adenomatous polyposis, a cancer predisposition syndrome caused by germline mutations in the adenomatous polyposis coli tumor suppressor gene. Patients with FAP develop adenomas and inevitably progress to invasive carcinomas by the age of 40. To better delineate the role of mucosal immunity in colorectal cancer, we evaluated the efficacy of intrarectal recombinant vaccinia virus expressing the human carcinoembryonic Ag (CEA) in a murine FAP model in which mice are predisposed to colorectal cancer and also express human CEA in the gut. Mucosal vaccination reduced the incidence of spontaneous adenomas and completely prevented progression to invasive carcinoma. The therapeutic effects were associated with induction of mucosal CEA-specific IgA Ab titers and CD8+ CTLs. Mucosal vaccination was also associated with an increase in systemic CEA-specific IgG Ab titers, CD4+ and CD8+ T cell responses and resulted in growth inhibition of s.c. implanted CEA-expressing tumors suggesting communication between mucosal and systemic immune compartments. Thus, intrarectal vaccination induces mucosal and systemic antitumor immunity and prevents progression of spontaneous colorectal cancer. These results have implications for the prevention of colorectal cancer in high-risk individuals.
Detection of Complement Activation on Antigen Microarrays Generates Functional Antibody Profiles and Helps Characterization of Disease-Associated Changes of the Antibody Repertoire
Authors: Papp Krisztián , Végh Péter , Miklós Kata , Németh Julianna , Rásky Klára , Péterfy Ferenc , Erdei Anna , Prechl József 
Published: April 2014

AbstractHumoral immune responses are traditionally characterized by determining the presence and quality of Abs specific for certain Ags. Arraying of large numbers of Ags allows the parallel measurement of Abs, generating patterns called Ab profiles. Functional characterization of these Abs could help draw an even more informative map of an immune response. To generate functional Ab profiles we simultaneously tested not only IgM, IgG, and IgA binding to, but also complement activation by, a panel of endogenous and exogenous Ags printed as microarrays, using normal and autoimmune human sera. We show that complement activation by a particular Ag in a given individual cannot be predicted by the measurement of Ag-specific Abs, despite a general correlation between the amount of Ag-bound Ab and the deposited C3 fragments. This is due to both differences in the isotypes that dominate in the recognition of an Ag and individual variations for a given isotype, resulting in altered complement activation potential. Thus, Ag-specific C3 deposition can be used as an additional parameter in immune response monitoring. This is exemplified by comparing the coordinates of Ags, used for the diagnosis of systemic lupus erythematosus, of normal and autoimmune serum samples in a two-dimensional space derived from C3 deposition and Ab binding. Since cleavage fragments of C3 mediate important immunological processes, we propose that measurement of their deposition on Ag microarrays, in addition to Ab profiling, can provide useful functional signature about the tested serum.
Regulated Movement of CD4 In and Out of the Immunological Synapse
Authors: Kao Henry , Lin Joseph , Littman Dan R. , Shaw Andrey S. , Allen Paul M. 
Published: April 2014

AbstractThe mechanism underlying the transient accumulation of CD4 at the immunological synapse (IS) and its significance for T cell activation are not understood. To investigate these issues, we mutated a serine phosphorylation site (S408) in the cytoplasmic tail of murine CD4. Preventing phosphorylation of S408 did not block CD4 recruitment to the IS; rather, it blocked the ability of CD4 to leave the IS. Surprisingly, enhanced and prolonged CD4 accumulation at the supramolecular activation cluster in the contact area had no functional consequence for T cell activation, cytokine production, or proliferation. Protein kinase C θ (PKCθ)-deficient T cells also displayed enhanced and prolonged accumulation of wild-type CD4 at the IS, indicating that θ is the critical PKC isoform involved in CD4 movement. These findings suggest a model wherein recruitment of CD4 to the IS allows its phosphorylation by PKCθ and subsequent removal from the IS. Thus, an important role for PKCθ in T cell activation involves its recruitment to the IS, where it phosphorylates specific substrates that help to maintain the dynamism of protein turnover at the IS.
B Lymphocytes Promote Expansion of Regulatory T Cells in Oral Tolerance: Powerful Induction by Antigen Coupled to Cholera Toxin B Subunit
Authors: Sun Jia-Bin , Flach Carl-Fredrik , Czerkinsky Cecil , Holmgren Jan 
Published: April 2014

AbstractMucosal administration of Ag conjugated to cholera toxin B subunit (CTB) can efficiently induce peripheral immunologic tolerance, so-called oral tolerance, associated with development of Foxp3+CD25+CD4+ regulatory T (Treg) cells. Using an established sublingual tolerization regimen with Ag(OVA)/CTB conjugate, wherein CTB mediates Ag uptake and presentation by most B lymphocytes irrespective of their Ag specificity, we have assessed the importance of B cells for induction of Ag-specific Treg cells and oral tolerance. We found that Treg cells are reduced in μMT−/− B cell-deficient mice compared with wild-type (WT) mice. After sublingual Ag/CTB treatment, Treg cells increased much more in WT than in μMT−/− mice; however, adoptive transfer of B cells before treatment normalized Treg cell development and functional oral tolerance. B cells from OVA/CTB-treated mice expressed more IL-10 and less CD86 than control B cells. Adoptive transfer of these cells before parenteral immunization with OVA led to efficient suppression of proliferation and to induction of apoptotic depletion of Ag-specific CD25−CD4+ effector T cells associated with the expansion of Treg cells. However, also OVA/CTB-treated μMT−/− mice could suppress the immune response to parenteral immunization with OVA, which was associated with a strong increase in Foxp3−CD4+ T cells expressing LAP/TGF-β. Our results indicate that mucosal tolerance comprises at least two separate pathways: one being B cell dependent and associated with expansion of Treg cells and Treg-mediated suppression and depletion of effector T cells, and one being B cell independent and associated with development of Foxp3−LAP+TGF-β+ regulatory T cells.
IP3 Receptor-Mediated Ca2+ Release in Naive CD4 T Cells Dictates Their Cytokine Program
Authors: Nagaleekar Viswas K. , Diehl Sean A. , Juncadella Ignacio , Charland Colette , Muthusamy Natarajan , Eaton Sheri , Haynes Laura , Garrett-Sinha Lee Ann , Anguita Juan , Rincón Mercedes 
Published: April 2014

AbstractIP3 (inositol 1,4,5-trisphosphate) receptors (IP3Rs) regulate the release of Ca2+ from intracellular stores in response to IP3. Little is known about regulation of the expression of IP3Rs and their role during the activation of CD4 T cells. In this study we show that mouse naive CD4 T cells express IP3R1, IP3R2, and IP3R3, but that gene expression of IP3R3 primarily is down-regulated upon activation due to loss of the Ets-1 transcription factor. Down-regulation of IP3R expression in activated CD4 T cells is associated with the failure of TCR ligation to trigger Ca2+ release in these cells. We also show that down-regulation of specific IP3Rs in activated CD4 T cells correlates with the requirement of IP3R-mediated Ca2+ release only for the induction of, but not for the maintenance of, IL-2 and IFN-γ expression. Interestingly, while inhibition of IP3R function early during activation blocks IL-2 and IFN-γ production, it promotes the production of IL-17 by CD4 T cells. Thus, IP3Rs play a key role in the activation and differentiation of CD4 T cells. The immunosuppressive effect of pharmacological blockers of these receptors may be complicated by promoting the development of inflammatory CD4 T cells.
T-Bet Dependent Removal of Sin3A-Histone Deacetylase Complexes at the Ifng Locus Drives Th1 Differentiation
Authors: Chang Shaojing , Collins Patrick L. , Aune Thomas M. 
Published: April 2014

Abstract
Forming and removing epigenetic histone marks at gene loci are central processes in differentiation. Here, we explored mechanisms establishing long-range H4 acetylation marks at the Ifng locus during Th1 lineage commitment. In Th0 cells, histone deacetylase (HDAC)-Sin3A complexes recruited to the Ifng locus actively prevented accumulation of H4 acetylation marks. Th1 differentiation caused loss of HDAC-Sin3A complexes by T-bet-dependent mechanisms and accumulation of H4 acetylation marks. HDAC-Sin3A complexes were absent from the locus in NOD Th0 cells, obviating the need for Th1 differentiation signals to establish histone marks and Th1 differentiation. Thus, Ifng transcription is actively prevented in Th0 cells via epigenetic mechanisms and epigenetic defects allow unregulated Ifng transcription that may contribute to autoimmunity.
IL-17A Enhances Vitamin D3-Induced Expression of Cathelicidin Antimicrobial Peptide in Human Keratinocytes
Authors: Peric Mark , Koglin Sarah , Kim Song-Min , Morizane Shin , Besch Robert , Prinz Jörg C. , Ruzicka Thomas , Gallo Richard L. , Schauber Jürgen 
Published: April 2014

Abstract
Cathelicidin is strongly expressed in lesional skin in psoriasis and may play an important role as both an antimicrobial peptide and as an autoinflammatory mediator in this chronic skin disease. The mechanism of increased cathelicidin in psoriatic keratinocytes is not known, but recent observations have found that psoriasis has abundant Th17 cells that produce IL-17A and IL-22. We found that human keratinocytes stimulated with supernatants from T cells isolated from lesional psoriatic skin increased expression of cathelicidin when stimulated in the presence of 1,25-dihydroxyvitamin D3 (1,25D3). This increase was signaled through the IL-17RA. In vitro, IL-17A, but not IL-22, enhanced cathelicidin mRNA and peptide expression in keratinocytes dependent on the presence of 1,25D3. At the same time, coincubation with 1,25D3 blocked induction of human β-defensin 2 (HBD2), IL-6, and IL-8, which are other target genes of IL-17A. Act1, an adaptor associated with IL-17RA and essential for IL-17A signaling, mediated cathelicidin induction, as its suppression by small interfering RNA inhibited HBD2 and cathelicidin. Both, 1,25D3 and IL-17A signaled cathelicidin induction through MEK-ERK. These results suggest that increased IL-17A in psoriatic skin increases cathelicidin through a vitamin D3-, Act1-, and MEK-ERK-dependent mechanism. Therapy targeting this cathelicidin-regulating system might be beneficial in patients suffering from psoriasis.