bluuebunny/crossref_metadata_2025_split huggingface dataset:
Protein Kinase Cα-Mediated Chemotaxis of Neutrophils Requires NF-κB Activity but Is Independent of TNFα Signaling in Mouse Skin In Vivo
Authors: Cataisson Christophe , Pearson Andrea J. , Torgerson Sara , Nedospasov Sergei A. , Yuspa Stuart H. 
Published: April 2014

Abstract
Protein kinase C (PKC) isoforms are major regulators of cutaneous homeostasis and mediate inflammation in response to 12-O-tetradecanoylphorbol-13-acetate (TPA). We have previously reported that transgenic mice overexpressing PKCα in the skin exhibit severe intraepidermal neutrophilic inflammation and keratinocyte apoptosis when treated topically with TPA. Activation of PKCα increases the production of TNFα and the transcription of chemotactic factors (MIP-2, KC, S100A8/A9), vascular endothelial growth factor, and GM-CSF in K5-PKCα keratinocytes. In response to PKCα activation, NF-κB translocates to the nucleus and this is associated with IκB phosphorylation and degradation. Preventing IκB degradation reduces both the expression of inflammation-associated genes and chemoattractant release. To determine whether TNFα mediated NF-κB translocation and subsequent expression of proinflammatory factors, K5-PKCα mice were treated systemically with a dimeric soluble form of p75 TNFR (etanercept) or crossed with mice deficient for both TNFR isoforms, and keratinocytes were cultured in the presence of TNFα-neutralizing Abs. The in vivo treatment and TNFR deficiency did not prevent inflammation, and the in vitro treatment did not prevent NF-κB nuclear translocation after TPA. Together these results implicate PKCα as a regulator of a subset of cutaneous cytokines and chemokines responsible for intraepidermal inflammation independent of TNFα. PKCα inhibition may have therapeutic benefit in some human inflammatory skin disorders.
CCL18 Is Expressed in Atopic Dermatitis and Mediates Skin Homing of Human Memory T Cells
Authors: Günther Claudia , Bello-Fernandez Concha , Kopp Tamara , Kund Julia , Carballido-Perrig Nicole , Hinteregger Sonja , Fassl Sandra , Schwärzler Christoph , Lametschwandtner Günther , Stingl Georg , Biedermann Tilo , Carballido José M. 
Published: April 2014

AbstractCCL18 is a human chemokine secreted by monocytes and dendritic cells. The receptor for CCL18 is not yet known and the functions of this chemokine on immune cells are not fully elucidated. In this study, we describe that CCL18 is present in skin biopsies of atopic dermatitis (AD) patients but not in normal or psoriatic skin. CCL18 was specifically expressed by APCs in the dermis and by Langerhans and inflammatory dendritic epidermal cells in the epidermis. In addition, the serum levels of CCL18 and the percentages of CCL18-producing monocyte/macrophages and dendritic cells were significantly increased in AD patients compared with healthy controls. Furthermore, we demonstrate that CCL18 binds to CLA+ T cells in peripheral blood of AD patients and healthy individuals and induces migration of AD-derived memory T cells in vitro and in human skin-transplanted SCID mice. These findings highlight a unique role of CCL18 in AD and reveal a novel function of this chemokine mediating skin homing of a subpopulation of human memory T cells.
IFN-γ at the Site of Infection Determines Rate of Clearance of Infection in Cryptococcal Meningitis
Authors: Siddiqui Asna A. , Brouwer Annemarie E. , Wuthiekanun Vannaporn , Jaffar Shabbar , Shattock Robin , Irving Diane , Sheldon Joanna , Chierakul Wirongrong , Peacock Sharon , Day Nicholas , White Nicholas J. , Harrison Thomas S. 
Published: April 2014

Abstract
In animal models, immunity to cryptococcal infection, as in many chronic fungal and bacterial infections, is associated with a granulomatous inflammatory response, intact cell-mediated immunity, and a Th1 pattern of cytokine release. To examine the correlates of human immunity to cryptococcal infection in vivo, we analyzed immune parameters at the site of infection over time and assessed the rate of clearance of infection by serial quantitative cerebrospinal fluid (CSF) fungal cultures in 62 patients in a trial of antifungal therapy for HIV-associated cryptococcal meningitis. CSF IL-6, IFN-γ, TNF-α, and IL-8 were significantly higher in survivors compared with nonsurvivors. There were negative correlations between log TNF-α, IFN-γ, and IL-6 levels and baseline cryptococcal CFU. Log IFN-γ, G-CSF, TNF-α, and IL-6 were correlated positively with the rate of fall in log CFU/ml CSF/day. In a linear regression model including antifungal treatment group, baseline CFU, and these cytokines, only treatment group and log IFN-γ remained independently associated with rate of clearance of infection. The results provide direct in vivo evidence for the importance of quantitative differences in IFN-γ secretion in human immune control of granulomatous infections, and increase the rationale for adjunctive IFN-γ in the treatment of refractory HIV-associated cryptococcosis.
B Cell Selection and Susceptibility to Autoimmunity
Authors: Grimaldi Christine M. , Hicks Ruthmarie , Diamond Betty 
Published: April 2014

Abstract
Autoreactive B cells arise routinely as part of the naive B cell repertoire. The immune system employs several mechanisms in an attempt to silence these autoreactive cells before they achieve immunocompetence. The BCR plays a central role in B cell development, activation, survival, and apoptosis, and thus is a critical component of the regulation of both protective and autoreactive B cells. The strength of signal mediated by the BCR is determined by numerous factors, both B cell intrinsic and B cell extrinsic. Perturbations in the molecules that regulate the BCR signal strength or that activate pathways that engage in cross talk with the BCR-mediated signaling pathways can lead to the aberrant survival and activation of autoreactive B cells. In this review, we will discuss the some newly identified genetic loci and factors that modulate the BCR signal transduction pathway and, therefore, the regulation of autoreactive B cells. We will also provide evidence for a model of autoreactivity in which a reduction in the strength of the BCR signal allows the survival and the modulation of a naive B cell repertoire replete with autoreactivity.
Cutting Edge: Antibody Production to Pneumococcal Polysaccharides Requires CD1 Molecules and CD8+ T Cells
Authors: Kobrynski Lisa J. , Sousa Alexandra O. , Nahmias André J. , Lee Francis K. 
Published: April 2014

Abstract
T cell involvement in Ab responses to thymus-independent type 2 Ags is an immunologic enigma. The identity of these cells and the mechanisms of their TCR engagement to carbohydrate molecules remain unknown. We measured IgG Ab production after immunization with pneumococcal polysaccharides in mice with disruptions in selected genes of the T cell pathway. Nonclassical MHC class I-like CD1 molecules and MHC class I-dependent CD8+ cells were found to be essential. Our findings set forth a new paradigm for humoral responses in which CD1 expression as well as a subset of CD8+ cells are required to provide helper function for Ab production against thymus-independent type 2 polysaccharides, similar to MHC class II-restricted CD4+ cells for protein Ags.
Presentation of Endogenously Synthesized MHC Class II-Restricted Epitopes by MHC Class II Cancer Vaccines Is Independent of Transporter Associated with Ag Processing and the Proteasome
Authors: Dissanayake Samudra K. , Tuera Natalia , Ostrand-Rosenberg Suzanne 
Published: April 2014

Abstract
Cell-based vaccines consisting of invariant chain-negative tumor cells transfected with syngeneic MHC class II (MHC II) and costimulatory molecule genes are prophylactic and therapeutic agents for the treatment of murine primary and metastatic cancers. Vaccine efficacy is due to direct presentation of endogenously synthesized, MHC II-restricted tumor peptides to CD4+ T cells. Because the vaccine cells lack invariant chain, we have hypothesized that, unlike professional APC, the peptide-binding groove of newly synthesized MHC II molecules may be accessible to peptides, allowing newly synthesized MHC II molecules to bind peptides that have been generated in the proteasome and transported into the endoplasmic reticulum via the TAP complex. To test this hypothesis, we have compared the Ag presentation activity of multiple clones of TAP-negative and TAP-positive tumor cells transfected with I-Ak genes and the model Ag hen egg white lysozyme targeted to the endoplasmic reticulum or cytoplasm. Absence of TAP does not diminish Ag presentation of three hen egg white lysozyme epitopes. Likewise, cells treated with proteasomal and autophagy inhibitors are as effective APC as untreated cells. In contrast, drugs that block endosome function significantly inhibit Ag presentation. Coculture experiments demonstrate that the vaccine cells do not release endogenously synthesized molecules that are subsequently endocytosed and processed in endosomal compartments. Collectively, these data indicate that vaccine cell presentation of MHC II-restricted endogenously synthesized epitopes occurs via a mechanism independent of the proteasome and TAP complex, and uses a pathway that overlaps with the classical endosomal pathway for presentation of exogenously synthesized molecules.
Defective Proximal TCR Signaling Inhibits CD8+ Tumor-Infiltrating Lymphocyte Lytic Function
Authors: Koneru Mythili , Schaer David , Monu Ngozi , Ayala Aidee , Frey Alan B. 
Published: April 2014

AbstractCD8+ tumor-infiltrating lymphocytes (TIL) are severely deficient in cytolysis, a defect that may permit tumor escape from immune-mediated destruction. Because lytic function is dependent upon TCR signaling, we have tested the hypothesis that primary TIL have defective signaling by analysis of the localization and activation status of TIL proteins important in TCR-mediated signaling. Upon conjugate formation with cognate target cells in vitro, TIL do not recruit granzyme B+ granules, the microtubule-organizing center, F-actin, Wiskott-Aldrich syndrome protein, nor proline rich tyrosine kinase-2 to the target cell contact site. In addition, TIL do not flux calcium nor demonstrate proximal tyrosine kinase activity, deficiencies likely to underlie failure to fully activate the lytic machinery. Confocal microscopy and fluorescence resonance energy transfer analyses demonstrate that TIL are triggered by conjugate formation in that the TCR, p56lck, CD3ζ, LFA-1, lipid rafts, ZAP70, and linker for activation of T cells localize at the TIL:tumor cell contact site, and CD43 and CD45 are excluded. However, proximal TCR signaling is blocked upon conjugate formation because the inhibitory motif of p56lck is rapidly phosphorylated (Y505) and COOH-terminal Src kinase is recruited to the contact site, while Src homology 2 domain-containing protein phosphatase 2 is cytoplasmic. Our data support a novel mechanism explaining how tumor-induced inactivation of proximal TCR signaling regulates lytic function of antitumor T cells.
Cytokine Expanded Myeloid Precursors Function as Regulatory Antigen-Presenting Cells and Promote Tolerance through IL-10-Producing Regulatory T Cells
Authors: MacDonald Kelli P. A. , Rowe Vanessa , Clouston Andrew D. , Welply Joseph K. , Kuns Rachel D. , Ferrara James L. M. , Thomas Ranjeny , Hill Geoffrey R. 
Published: April 2014

Abstract
The initiation of graft-vs-host disease (GVHD) after stem cell transplantation is dependent on direct Ag presentation by host APCs, whereas the effect of donor APC populations is unclear. We studied the role of indirect Ag presentation in allogenic T cell responses by adding populations of cytokine-expanded donor APC to hemopoietic grafts that would otherwise induce lethal GVHD. Progenipoietin-1 (a synthetic G-CSF/Flt-3 ligand molecule) and G-CSF expanded myeloid dendritic cells (DC), plasmacytoid DC, and a novel granulocyte-monocyte precursor population (GM) that differentiate into class II+,CD80/CD86+,CD40− APC during GVHD. Whereas addition of plasmacytoid and myeloid donor DC augmented GVHD, GM cells promoted transplant tolerance by MHC class II-restricted generation of IL-10-secreting, Ag-specific regulatory T cells. Importantly, although GM cells abrogated GVHD, graft-vs-leukemia effects were preserved. Thus, a population of cytokine-expanded GM precursors function as regulatory APCs, suggesting that G-CSF derivatives may have application in disorders characterized by a loss of self-tolerance.
Development of Autoimmunity against Transcriptionally Unrepressed Target Antigen in the Thymus of Aire-Deficient Mice
Authors: Kuroda Noriyuki , Mitani Tasuku , Takeda Naoki , Ishimaru Naozumi , Arakaki Rieko , Hayashi Yoshio , Bando Yoshimi , Izumi Keisuke , Takahashi Takeshi , Nomura Takashi , Sakaguchi Shimon , Ueno Tomoo , Takahama Yousuke , Uchida Daisuke , Sun Shijie , Kajiura Fumiko , Mouri Yasuhiro , Han Hongwei , Matsushima Akemi , Yamada Gen , Matsumoto Mitsuru 
Published: April 2014

Abstract
Autoimmune regulator (AIRE) gene mutation is responsible for the development of organ-specific autoimmune disease with monogenic autosomal recessive inheritance. Although Aire has been considered to regulate the elimination of autoreactive T cells through transcriptional control of tissue-specific Ags in thymic epithelial cells, other mechanisms of AIRE-dependent tolerance remain to be investigated. We have established Aire-deficient mice and examined the mechanisms underlying the breakdown of self-tolerance. The production and/or function of immunoregulatory T cells were retained in the Aire-deficient mice. The mice developed Sjögren’s syndrome-like pathologic changes in the exocrine organs, and this was associated with autoimmunity against a ubiquitous protein, α-fodrin. Remarkably, transcriptional expression of α-fodrin was retained in the Aire-deficient thymus. These results suggest that Aire regulates the survival of autoreactive T cells beyond transcriptional control of self-protein expression in the thymus, at least against this ubiquitous protein. Rather, Aire may regulate the processing and/or presentation of self-proteins so that the maturing T cells can recognize the self-Ags in a form capable of efficiently triggering autoreactive T cells. With the use of inbred Aire-deficient mouse strains, we also demonstrate the presence of some additional factor(s) that determine the target-organ specificity of the autoimmune disease caused by Aire deficiency.
Prevention of Experimental Autoimmune Encephalomyelitis by Transfer of Embryonic Stem Cell-Derived Dendritic Cells Expressing Myelin Oligodendrocyte Glycoprotein Peptide along with TRAIL or Programmed Death-1 Ligand
Authors: Hirata Shinya , Senju Satoru , Matsuyoshi Hidetake , Fukuma Daiki , Uemura Yasushi , Nishimura Yasuharu 
Published: April 2014

AbstractExperimental autoimmune encephalomyelitis (EAE) is caused by activation of myelin Ag-reactive CD4+ T cells. In the current study, we tested a strategy to prevent EAE by pretreatment of mice with genetically modified dendritic cells (DC) presenting myelin oligodendrocyte glycoprotein (MOG) peptide in the context of MHC class II molecules and simultaneously expressing TRAIL or Programmed Death-1 ligand (PD-L1). For genetic modification of DC, we used a recently established method to generate DC from mouse embryonic stem cells (ES cells) in vitro (ES-DC). ES cells were sequentially transfected with an expression vector for TRAIL or PD-L1 and an MHC class II-associated invariant chain-based MOG epitope-presenting vector. Subsequently, double-transfectant ES cell clones were induced to differentiate to ES-DC, which expressed the products of introduced genes. Treatment of mice with either of the double-transfectant ES-DC significantly reduced T cell response to MOG, cell infiltration into spinal cord, and the severity of MOG peptide-induced EAE. In contrast, treatment with ES-DC expressing MOG alone, irrelevant Ag (OVA) plus TRAIL, or OVA plus PD-L1, or coinjection with ES-DC expressing MOG plus ES-DC-expressing TRAIL or PD-L1 had no effect in reducing the disease severity. In contrast, immune response to irrelevant exogenous Ag (keyhole limpet hemocyanin) was not impaired by treatment with any of the genetically modified ES-DC. The double-transfectant ES-DC presenting Ag and simultaneously expressing immune-suppressive molecules may well prove to be an effective therapy for autoimmune diseases without inhibition of the immune response to irrelevant Ag.
Cross-Linking of 4-1BB Activates TCR-Signaling Pathways in CD8+ T Lymphocytes
Authors: Nam Kyung-Ok , Kang Hyun , Shin Su-Mi , Cho Kwang-Hyun , Kwon Byoungsuk , Kwon Byoung S. , Kim Sung-Jin , Lee Hyeon-Woo 
Published: April 2014

Abstract
Cross-linking of 4-1BB, a member of the TNFR family, increased tyrosine phosphorylation of TCR-signaling molecules such as CD3ε, CD3ζ, Lck, the linker for activation of T cells, and SH2 domain-containing leukocyte phosphoprotein of 76 kDa (SLP-76). In addition, incubation of activated CD8+ T cells with p815 cells expressing 4-1BBL led to redistribution of the lipid raft domains and Lck, protein kinase C-θ, SLP-76, and phospholipase C-γ1 (PLC-γ1) on the T cell membranes to the areas of contact with the p815 cells and recruitment of 4-1BB, TNFR-associated factor 2, and phospho-tyrosine proteins to the raft domains. 4-1BB ligation also caused translocation of TNFR-associated factor 2, protein kinase C-θ, PLC-γ1, and SLP-76 to detergent-insoluble compartments in the CD8+ T cells, and cross-linking of 4-1BB increased intracellular Ca2+ levels apparently by activating PLC-γ1. The redistribution of lipid rafts and Lck, as well as translocation of PLC-γ1, and degradation of IκB-α in response to 4-1BB were inhibited by disrupting the formation of lipid rafts with methyl-β-cyclodextrin. These findings demonstrate that 4-1BB is a T cell costimulatory receptor that activates TCR-signaling pathways in CD8+ T cells.
Inhibition of T Cell Differentiation into Effectors by NKT Cells Requires Cell Contacts
Authors: Novak Jan , Beaudoin Lucie , Griseri Thibault , Lehuen Agnès 
Published: April 2014

Abstract
NKT cells are potent regulatory T cells that prevent the development of several autoimmune diseases. Analysis of NKT cell regulatory function in the NOD mouse has revealed that NKT cells inhibit the development of type 1 diabetes by impairing the differentiation of anti-islet T cells into Th1 effector cells. In the present study, we have performed in vitro and in vivo experiments to determine the respective role of cytokines and cell contacts in the blockade of T cell differentiation by NKT cells. These experiments reveal that cytokines such as IL-4, IL-10, IL-13, and TGF-β, that have been involved in other functions of NKT cells, play only a minor role if any in the blockade of T cell differentiation by NKT cells. Diabetes is still prevented by NKT cells in the absence of functional IL-4, IL-10, IL-13, and TGF-β. In contrast, we show for the first time that cell contacts are crucial for the immunoregulatory function of NKT cells.
A T Lymphocyte-Specific Transcription Complex Containing RUNX1 Activates MHC Class I Expression
Authors: Howcroft T. Kevin , Weissman Jocelyn D. , Gegonne Anne , Singer Dinah S. 
Published: April 2014

Abstract
MHC class I expression is subject to both tissue-specific and hormonal regulatory mechanisms. Consequently, levels of expression vary widely among tissues, with the highest levels of class I occurring in the lymphoid compartment, in T cells and B cells. Although the high class I expression in B cells is known to involve the B cell enhanceosome, the molecular basis for high constitutive class I expression in T cells has not been explored. T cell-specific genes, such as TCR genes, are regulated by a T cell enhanceosome consisting of RUNX1, CBFβ, LEF1, and Aly. In this report, we demonstrate that MHC class I gene expression is enhanced by the T cell enhanceosome and results from a direct interaction of the RUNX1-containing complex with the class I gene in vivo. T cell enhanceosome activation of class I transcription is synergistic with CIITA-mediated activation and targets response elements distinct from those targeted by CIITA. These findings provide a molecular basis for the high levels of MHC class I in T cells.
Granzyme B and the Downstream Granzymes C and/or F Are Important for Cytotoxic Lymphocyte Functions
Authors: Revell Paula A. , Grossman William J. , Thomas Dori A. , Cao Xuefang , Behl Rajesh , Ratner Jane A. , Lu Zhi Hong , Ley Timothy J. 
Published: April 2014

Abstract
Although the functions of granzyme A (GzmA) and GzmB are well-defined, a number of orphan granzymes of unknown function are also expressed in cytotoxic lymphocytes. Previously, we showed that a targeted loss-of-function mutation for GzmB was associated with reduced expression of several downstream orphan granzyme genes in the lymphokine-activated killer cell compartment. To determine whether this was caused by the retained phosphoglycerate kinase I gene promoter (PGK-neo) cassette in the GzmB gene, we retargeted the GzmB gene with a LoxP-flanked PGK-neo cassette, then removed the cassette in embryonic stem cells by transiently expressing Cre recombinase. Mice homozygous for the GzmB null mutation containing the PGK-neo cassette (GzmB−/−/+PGK-neo) displayed reduced expression of the closely linked GzmC and F genes in their MLR-derived CTLs and lymphokine-activated killer cells; removal of the PGK-neo cassette (GzmB−/−/ΔPGK-neo) restored the expression of both genes. Cytotoxic lymphocytes derived from mice with the retained PGK-neo cassette (GzmB−/−/+PGK-neo) had a more severe cytotoxic defect than those deficient for GzmB only (GzmB−/−/ΔPGK-neo). Similarly, GzmB−/−/+PGK-neo mice displayed a defect in the allogeneic clearance of P815 tumor cells, whereas GzmB−/−/ΔPGK-neo mice did not. These results suggest that the retained PGK-neo cassette in the GzmB gene causes a knockdown of GzmC and F expression, and also suggest that these granzymes are relevant for the function of cytotoxic lymphocytes in vitro and in vivo.
Highly Focused T Cell Responses in Latent Human Pulmonary Mycobacterium tuberculosis Infection
Authors: Tully Glenn , Kortsik Cornelius , Höhn Hanni , Zehbe Ingeborg , Hitzler W. E. , Neukirch Claudia , Freitag Kirsten , Kayser Klaus , Maeurer Markus J. 
Published: April 2014

Abstract
The elucidation of the molecular and immunological mechanisms mediating maintenance of latency in human tuberculosis aids to develop more effective vaccines and to define biologically meaningful markers for immune protection. We analyzed granuloma-associated lymphocytes (GALs) from human lung biopsies of five patients with latent Mycobacterium tuberculosis (MTB) infection. MTB CD4+ and CD8+ T cell response was highly focused in the lung, distinct from PBL, as assessed by TCR-CDR3 spectratyping coupled with a quantitative analysis of TCR VB frequencies. GALs produced IFN-γ in response to autologous macrophages infected with MTB and to defined MTB-derived HLA-A2-presented peptides Ag85a242–250, Ag85b199–207, early secreted antigenic target 6 (ESAT-6)28–36, 19-kDa Ag88–97, or the HLA-DR-presented ESAT-61–20 epitope. Immune recognition of naturally processed and presented MTB epitopes or the peptide ESAT-61–20 could be linked to specific TCR VB families, and in two patients to unique T cell clones that constituted 19 and 27%, respectively, of the CD4+ and 17% of the CD8+ GAL population. In situ examination of MTB-reactive GALs by tetramer in situ staining and confocal laser-scanning microscopy consolidates the presence of MHC class I-restricted CD8+ T cells in MTB granuloma lesions and supports the notion that clonally expanded T cells are crucial in immune surveillance against MTB.