bluuebunny/crossref_metadata_2025_split huggingface dataset:
Skin Inflammation During Contact Hypersensitivity Is Mediated by Early Recruitment of CD8+ T Cytotoxic 1 Cells Inducing Keratinocyte Apoptosis
Authors: Akiba Hitoshi , Kehren Jeanne , Ducluzeau Marie-Thérèse , Krasteva Maya , Horand Françoise , Kaiserlian Dominique , Kaneko Fumio , Nicolas Jean-François 
Published: April 2014

AbstractContact hypersensitivity (CHS) is a T cell-mediated, Ag-specific skin inflammation induced by skin exposure to haptens in sensitized individuals. Th1/T cytotoxic 1 cells are effector cells of CHS, whereas Th2/T regulatory CD4+ T cells have down-regulating properties. We have previously shown that CHS to 2,4-dinitrofluorobenzene is mediated by specific CD8+ effector cells, whose cytolytic activity is mandatory for induction of skin inflammation. In this study, using immunohistochemistry and RT-PCR analysis, we show that CD8+ T cells are rapidly recruited into the skin at the site of hapten challenge before the onset of clinical and histological signs of skin inflammation. This early CD8+ T cell recruitment is concomitant with: 1) transient IFN-γ mRNA expression suggesting local activation of effector cells; and 2) induction of keratinocyte (KC) apoptosis which gradually increased to a maximum at the peak of the CHS response. Alternatively, skin infiltration of CD4+ T cells occurred later and coincided with the peak of the CHS reaction and the beginning of the resolution of skin inflammation. Mice deficient in CD8+ T cells did not develop CHS, whereas mice deficient in CD4+ T cells developed an enhanced inflammatory response with increased numbers of CD8+ T cells recruited in the skin associated with massive KC apoptosis. These data show that CHS is due to the early and selective recruitment in the skin of CD8+ T cytotoxic 1 effector cells responsible for KC apoptosis.
Syk Regulation of Phosphoinositide 3-Kinase-Dependent NK Cell Function
Authors: Jiang Kun , Zhong Bin , Gilvary Danielle L. , Corliss Brian C. , Vivier Eric , Hong-Geller Elizabeth , Wei Sheng , Djeu Julie Y. 
Published: April 2014

AbstractEmerging evidence suggests that NK-activatory receptors use KARAP/DAP12, CD3ζ, and FcεRIγ adaptors that contain immunoreceptor tyrosine-based activatory motifs to mediate NK direct lysis of tumor cells via Syk tyrosine kinase. NK cells may also use DAP10 to drive natural cytotoxicity through phosphoinositide 3-kinase (PI3K). In contrast to our recently identified PI3K pathway controlling NK cytotoxicity, the signaling mechanism by which Syk associates with downstream effectors to drive NK lytic function has not been clearly defined. In NK92 cells, which express DAP12 but little DAP10/NKG2D, we now show that Syk acts upstream of PI3K, subsequently leading to the specific signaling of the PI3K→Rac1→PAK1→mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase→ERK cascade that we earlier described. Tumor cell ligation stimulated DAP12 tyrosine phosphorylation and its association with Syk in NK92 cells; Syk tyrosine phosphorylation and activation were also observed. Inhibition of Syk function by kinase-deficient Syk or piceatannol blocked target cell-induced PI3K, Rac1, PAK1, mitogen-activated protein/ERK kinase, and ERK activation, perforin movement, as well as NK cytotoxicity, indicating that Syk is upstream of all these signaling events. Confirming that Syk does not act downstream of PI3K, constitutively active PI3K reactivated all the downstream effectors as well as NK cytotoxicity suppressed in Syk-impaired NK cells. Our results are the first report documenting the instrumental role of Syk in control of PI3K-dependent natural cytotoxicity.
Suppressors of Cytokine Signaling Proteins Are Differentially Expressed in Th1 and Th2 Cells: Implications for Th Cell Lineage Commitment and Maintenance
Authors: Egwuagu Charles E. , Yu Cheng-Rong , Zhang Meifen , Mahdi Rashid M. , Kim Stephen J. , Gery Igal 
Published: April 2014

AbstractPositive regulatory factors induced by IL-12/STAT4 and IL-4/STAT6 signaling during T cell development contribute to polarized patterns of cytokine expression manifested by differentiated Th cells. These two critical and antagonistic signaling pathways are under negative feedback regulation by a multimember family of intracellular proteins called suppressor of cytokine signaling (SOCS). However, it is not known whether these negative regulatory factors also modulate Th1/Th2 lineage commitment and maintenance. We show here that CD4+ naive T cells constitutively express low levels of SOCS1, SOCS2, and SOCS3 mRNAs. These mRNAs and their proteins increase significantly in nonpolarized Th cells after activation by TCR signaling. We further show that differentiation into Th1 or Th2 phenotype is accompanied by preferential expression of distinct SOCS mRNA transcripts and proteins. SOCS1 expression is 5-fold higher in Th1 than in Th2 cells, whereas Th2 cells contain 23-fold higher levels of SOCS3. We also demonstrate that IL-12-induced STAT4 activation is inhibited in Th2 cells that express high levels of SOCS3 whereas IL-4/STAT6 signaling is constitutively activated in Th2 cells, but not Th1 cells, with high SOCS1 expression. These results suggest that mutually exclusive use of STAT4 and STAT6 signaling pathways by differentiated Th cells may derive in part, from SOCS3- or SOCS1-mediated repression of IL-12/STAT4- or IL-4/STAT6 signaling in Th2 and Th1 cells, respectively. Given the strong correlation between distinct patterns of SOCS expression and differentiation into the Th1 or Th2 phenotype, SOCS1 and SOCS3 proteins are therefore Th lineage markers that can serve as therapeutic targets for immune modulation therapy.
Autoreactive T Cells Revealed in the Normal Repertoire: Escape from Negative Selection and Peripheral Tolerance
Authors: Yan Jun , Mamula Mark J. 
Published: April 2014

AbstractSelf-reactive T cells are known to be eliminated by negative selection in the thymus or by the induction of tolerance in the periphery. However, developmental pathways that allow self-reactive T cells to inhabit the normal repertoire are not well-characterized. In this investigation, we made use of anti-small nuclear ribonucleoprotein particle (snRNP) Ig transgenic (Tg) mice (2-12 Tg) to demonstrate that autoreactive T cells can be detected and activated in both normal naive mice and autoimmune-prone MRL lpr/lpr mice. In contrast, autoreactive T cells of nonautoimmune Tg mice are tolerized by Tg B cells in the periphery. In adoptive transfer studies, autoreactive T cells from MRL lpr/lpr mice can stimulate autoantibody synthesis in nonautoimmune anti-snRNP Tg mice. Transferred CD4 T cells migrate to regions of the spleen proximal to the B cell follicles, suggesting that cognate B cell-T cell interactions are critical to the autoimmune response. Taken together, our studies suggest that anti-snRNP B cells are important APCs for T cell activation in autoimmune-prone mice. Additionally, we have demonstrated that anti-snRNP B cell anergy in nonautoimmune mice may be reversed by appropriate T cell help.
Functional Consequences of Noncognate Interactions Between CD4+ Memory T Lymphocytes and the Endothelium
Authors: Berg Lutz-Peter , James Martha J. , Alvarez-Iglesias Montserrat , Glennie Sarah , Lechler Robert I. , Marelli-Berg Federica M. 
Published: April 2014

AbstractThe recruitment of Ag-specific T cells to sites of inflammation is a crucial step in immune surveillance. Although the molecular interactions controlling T cell extravasation are relatively well characterized, the effects of these events on T cell function are still poorly understood. Using an in vitro model of transendothelial migration of human CD4+ memory T cells, we have investigated the molecular and functional changes induced in T cells that come into contact with the endothelium. First, we show that transendothelial migration is precluded by signals that lead to T cell division. In addition, activation of the transcription factor AP-1, without induction of NF-κB, is observed in T cells after noncognate interactions with endothelial cells (EC), a pattern of transcriptional regulation different from that observed in dividing T cells. Up-regulation of certain adhesion (CD11a, CD49d), activation (CD69), and costimulatory (CD86) receptors accompany these transcriptional events. Most importantly, recently migrated T cells display a faster rate of migration when reseeded onto an EC monolayer. Finally, T cells become hyperresponsive to antigenic challenge after noncognate interactions with the endothelium. These effects appear not to be due to the selection of preactivated T lymphocytes, because they occur also in clonal T cell populations and appear to be mediated by αLβ2 integrin-CD54 interactions. We conclude that CD4+ memory T cell extravasation is accompanied by phenotypic and functional changes induced by the interactions with the EC, which favor tissue infiltration by T cells and their further activation once they reach the antigenic site.
Intracellular Domains of Target Antigens Influence Their Capacity to Trigger Antibody-Dependent Cell-Mediated Cytotoxicity
Authors: Tiroch Klaus , Stockmeyer Bernhard , Frank Carola , Valerius Thomas 
Published: April 2014

Abstract
Ab-mediated signaling in tumor cells and Ab-dependent cell-mediated cytotoxicity (ADCC) are both considered as relevant effector mechanisms for Abs in tumor therapy. To address potential interactions between these two mechanisms, we generated HER-2/neu- and CD19-derived chimeric target Ags, which were expressed in experimental tumor target cells. HER-2/neu-directed Abs were documented to mediate effective ADCC with both mononuclear cells (MNCs) and polymorphonuclear granulocytes (PMNs), whereas Abs against CD19 were effective only with MNCs and not with PMNs. We generated cDNA encoding HER-2/CD19 or CD19/HER-2 (extracellular/intracellular) chimeric fusion proteins by combining cDNA encoding extracellular domains of HER-2/neu or CD19 with intracellular domains of CD19 or HER-2/neu, respectively. After transfecting wild-type HER-2/neu or chimeric HER-2/CD19 into Raji Burkitt’s lymphoma cells and wild-type CD19 or chimeric CD19/HER-2 into SK-BR-3 breast cancer cells, target cell lines were selected for high membrane expression of transfected Ags. We then investigated the efficacy of tumor cell lysis by PMNs or MNCs with CD19- or HER-2/neu-directed Ab constructs. MNCs triggered effective ADCC against target cells expressing wild-type or chimeric target Ag. As expected, PMNs killed wild-type HER-2/neu-transfected, but not wild-type CD19-transfected target cells. Interestingly, however, PMNs were also effective against chimeric CD19/HER-2-transfected, but not HER-2/CD19-transfected target cells. In conclusion, these results demonstrate that intracellular domains of target Ags contribute substantially to effective Ab-mediated tumor cell killing by PMNs.
Uncoupling of Proliferation and Stat5 Activation in Thymic Stromal Lymphopoietin-Mediated Signal Transduction
Authors: Isaksen Deborah E. , Baumann Heinz , Zhou Baohua , Nivollet Sebastien , Farr Andrew G. , Levin Steven D. , Ziegler Steven F. 
Published: April 2014

AbstractThymic stromal lymphopoietin (TSLP) is a cytokine that facilitates B lymphocyte differentiation and costimulates T cells. Previous studies have demonstrated that a functional TSLP receptor complex is a heterodimer consisting of the TSLP receptor and the IL-7R α-chain. TSLP-mediated signaling is unique among members of the cytokine receptor family in that activation of the transcription factor Stat5 occurs without detectable Janus kinase activation. Using a variety of biological systems we demonstrate here that TSLP-mediated Stat5 activation can be uncoupled from proliferation. We also show that the single tyrosine residue in the cytoplasmic domain of the TSLP receptor is critical for TSLP-mediated proliferation, but is dispensable for Stat5 activation. Our data demonstrate that TSLP-mediated Stat5 activation is insufficient for cell proliferation and identifies residues within the TSLP receptor complex required to mediate these downstream events.
Clonal Selection, Clonal Senescence, and Clonal Succession: The Evolution of the T Cell Response to Infection with a Persistent Virus
Authors: Davenport Miles P. , Fazou Chrysoula , McMichael Andrew J. , Callan Margaret F. C. 
Published: April 2014

Abstract
We have analyzed the CD8+ T cell response to EBV and find that a larger primary burst size is associated with proportionally greater decay during the development of memory. Consequently, immunodominance and clonal dominance are less marked in memory than primary responses. An intuitive interpretation of this finding is that there is a limit to the number of cell divisions a T cell clone can undergo, and that the progeny of clones that have expanded massively during a primary immune response are more prone to die as a result of senescence. To test this hypothesis, we have derived a mathematical model of the response of different T cell clones of varying avidity for Ag in the primary and persistent phases of viral infection. When cellular survival and replication are linked to T cell avidity for Ag and Ag dose, then high-avidity T cells dominate both the primary and secondary responses. We then incorporated a limit in the number of cell divisions of individual T cell clones to test whether such a constraint could reproduce the observed association between cell division number and alterations in the contribution of clones to the response to persistent infection. Comparison of the model output with the experimental results obtained from primary and persistent EBV infection suggests that there is indeed a role for cellular senescence in shaping the immune response to persistent infection.
Bob1 (OCA-B/OBF-1) Differential Transactivation of the B Cell-SpecificB29(Igβ) andmb-1(Igα) Promoters
Authors: Malone Cindy Sue , Wall Randolph 
Published: April 2014

AbstractThe B29 (Igβ) and mb-1 (Igα) gene products are B cell-specific essential components of the B cell receptor that are coexpressed at all stages of B cell differentiation, with the exception of plasma cells, which lack mb-1 expression. Transcription of both genes is governed by a similar cassette of interactive transcription factor-binding elements, including octamer motifs, in TATA-less promoters. In this study, we show the B cell-specific B29 gene promoter is transactivated in B and non-B cells by cotransfection with the B cell-specific octamer cofactor gene, Bob1 (OCA-B/OBF-1). The expression of Bob1 is also sufficient to override the silencing effects of the B29 silencer. This indicates that Bob1 plays a critical role in B cell-specific B29 promoter expression. In contrast, coexpression of Bob1 had no effect on mb-1 promoter activity. Bob1 transactivation only occurs with select octamer sequences that have an adenosine at position 5 (ATGCAAAT). The B29 promoter conforms to this consensus octamer motif, while the mb-1 promoter octamer motif does not. Octamer motif swapping between B29 and mb-1 promoters renders B29 unresponsive to Bob1 transactivation and makes mb-1 competent for Bob1 transactivation, thereby indicating that the B29 octamer motif is solely responsible for Bob1 interaction. Additionally, the mb-1 construct containing the B29 octamer motif is expressed in a plasmacytoma cell line, while the wild-type mb-1 promoter is not. Bob1 transactivation of B29 and the lack of this transactivation of mb-1 account for the differential expression of B29 and mb-1 in terminally differentiated plasma cells.
Autocrine Deactivation of Macrophages in Transgenic Mice Constitutively Overexpressing IL-10 Under Control of the Human CD68 Promoter
Authors: Lang Roland , Rutschman Robert L. , Greaves David R. , Murray Peter J. 
Published: April 2014

AbstractIL-10 plays an essential role in blocking cytokine production by activated macrophages. To analyze the consequences of enforced expression of IL-10 by macrophages on innate and adaptive immune responses, we generated transgenic mice (macIL-10tg mice) expressing an epitope-tagged IL-10 (Flag-IL-10) under control of the human CD68 promoter. Expression of Flag-IL-10 was constitutive and restricted to macrophages, as shown by sorting splenocyte cell populations and intracellular staining for IL-10. Transgenic macrophages displayed suppressed production of TNF-α and IL-12 upon stimulation with LPS. When macIL-10tg mice were challenged with LPS, serum levels of proinflammatory cytokines were attenuated compared with controls. Infection with Mycobacterium bovis bacille Calmette-Guérin resulted in ∼10-fold-higher bacterial loads than in wild-type mice. Normal T and B cell responses were observed in macIL-10tg mice, suggesting that macrophage-specific overexpression of IL-10 predominantly acts in an autocrine/paracrine manner, resulting in chronically deactivated macrophages that manifest an impaired ability to control pathogens.
Increased Survival in Sepsis by In Vivo Adenovirus-Induced Expression of IL-10 in Dendritic Cells
Authors: Oberholzer Andreas , Oberholzer Caroline , Bahjat Keith S. , Ungaro Ricardo , Tannahill Cynthia L. , Murday Michelle , Bahjat Frances R. , Abouhamze Zaher , Tsai Van , LaFace Drake , Hutchins Beth , Moldawer Lyle L. , Clare-Salzler Michael J. 
Published: April 2014

Abstract
The dendritic cell (DC) is the most potent APC of the immune system, capable of stimulating naive T cells to proliferate and differentiate into effector T cells. Recombinant adenovirus (Adv) readily transduces DCs in vitro allowing directed delivery of transgenes that modify DC function and immune responses. In this study we demonstrate that footpad injection of a recombinant Adv readily targets transduction of myeloid and lymphoid DCs in the draining popliteal lymph node, but not in other lymphoid organs. Popliteal DCs transduced with an empty recombinant Adv undergo maturation, as determined by high MHC class II and CD86 expression. However, transduction with vectors expressing human IL-10 limit DC maturation and associated T cell activation in the draining lymph node. The extent of IL-10 expression is dose dependent; transduction with low particle numbers (105) yields only local expression, while transduction with higher particle numbers (107 and 1010) leads additionally to IL-10 appearance in the circulation. Furthermore, local DC expression of human IL-10 following in vivo transduction with low particle numbers (105) significantly improves survival following cecal ligation and puncture, suggesting that compartmental modulation of DC function profoundly alters the sepsis-induced immune response.
The IFN-Inducible Golgi- and Endoplasmic Reticulum- Associated 47-kDa GTPase IIGP Is Transiently Expressed During Listeriosis
Authors: Zerrahn Jens , Schaible Ulrich E. , Brinkmann Volker , Guhlich Ute , Kaufmann Stefan H. E. 
Published: April 2014

AbstractMembers of the 47-kDa GTPase family are implicated in an IFN-γ-induced, as yet unclear, mechanism that confers innate resistance against infection with intracellular pathogens. Overt immunological parameters are apparently uncompromised in mice deficient for individual members and the prototype of this family, IGTP, localizes to the endoplasmic reticulum. This suggests that these GTPases are involved in intracellular defense. We analyzed the expression of the 47-kDa GTPase cognate, IIGP, in splenic sections from mice infected with the intracellular pathogen Listeria monocytogenes by immunohistochemistry. An early transient IIGP induction was observed revealing the IFN-γ responsiveness of cellular subcompartments within the spleen in early listeriosis. Marginal metallophilic macrophages and endothelial cells within the red and white pulp strongly expressed IIGP, while other splenocytes remained negative. In vitro analyses show that both type I and type II IFNs are prime stimuli for IIGP induction in various cells, including L. monocytogenes-infected or LPS-stimulated macrophages, endothelial cells, and activated T cells. Contrary to the subcellular localization of IGTP, IIGP was predominantly associated with the Golgi apparatus and also localizes to the endoplasmic reticulum. We conclude that IIGP exerts a distinct role in IFN-induced intracellular membrane trafficking or processing.
γ3 Gene-Disrupted Mice Selectively Deficient in the Dominant IgG Subclass Made to Bacterial Polysaccharides. II. Increased Susceptibility to Fatal Pneumococcal Sepsis Due to Absence of Anti-Polysaccharide IgG3 Is Corrected by Induction of Anti-Polysaccharide IgG1
Authors: McLay John , Leonard Ethan , Petersen Sheryl , Shapiro David , Greenspan Neil S. , Schreiber John R. 
Published: April 2014

AbstractBacterial polysaccharides (PS) are type 2 T-independent Ags that elicit Abs restricted in isotype to IgM and predominantly IgG2 in humans and IgM, and IgG3 in mice. Humans with IgG2 subclass deficiency are susceptible to sinus and pulmonary infections with PS-encapsulated bacteria. We previously developed an IgG3-deficient mouse by disrupting the γ3 H chain constant region gene via targeted mutagenesis. Mutant mice lacking IgG3 were backcrossed for 10 generations to wild-type (WT) BALB/c mice to generate BALB/c mice that have complete absence of IgG3. WT mice immunized with type 3 Streptococcus pneumoniae capsular PS made anti-PS IgM, IgG3, and small quantities of IgG1, which opsonized S. pneumoniae for killing by polymorphonuclear leukocytes. These mice were protected against death from lethal doses of type 3 S. pneumoniae. In contrast, IgG3−/− mice made similar titers of anti-PS IgM and IgG1 as WT mice but no IgG3, and had poorly opsonic sera with significantly increased mortality after S. pneumoniae challenge. Immunization of IgG3−/− mice with type 3 S. pneumoniae PS conjugated to carrier protein CRM197-elicited IgM and high-titer IgG1 Abs, restored serum opsonization, and gave protection from mortality after S. pneumoniae, challenge comparable to WT mice. We conclude that mice lacking the dominant IgG3 subclass made to bacterial PS are more susceptible to fatal S. pneumoniae sepsis than WT mice, but that IgG1 induced by a S. pneumoniae glycoconjugate can adequately protect against S. pneumoniae sepsis. This model suggests that IgG subclass of anti-PS Ab is an important component of immunity to encapsulated bacteria.