bluuebunny/crossref_metadata_2025_split huggingface dataset:
The mouse immunoglobulin ϰ locus contains about 140 variable gene segments
Authors: Kirschbaum Thomas , Jaenichen Rita , Zachau Hans G. 
Published: March 2007

AbstractIn continuation of our efforts to elucidate the immunoglobulin ϰ locus of the mouse we analyzed 46 yeast artificial chromosomes (YACs) containing Vϰ, Jϰ and Cϰ genes. The YACs, which were derived from DNA of C57BL/6 and C3H mice, ranged from 0.3–1.9 Mb in size. On the basis of hybridization with probes specific for the Vϰ gene families a group of 13 YACs was selected for detailed analysis. The Vϰ genes of the YACs were then characterized by hybridization to the family‐specific probes and by the sizes of the EcoRI fragments on which they were found. This way evidence was obtained for 140 different Vϰ gene signals on the YACs. Of these 63 had been characterized before on clones from a cosmid library of total mouse DNA (I. Zocher et al., Eur. J. Immunol. 1995. 25: 3326–3331) and 22 others were found now on cosmid clones derived from the YACs. Six Vϰ genes of the previous study which were not found on the YACs are probably located outside of the ϰ locus. The YACs were arrayed in a unique order establishing a YACs panel which most likely contains the whole ϰ locus. The cosmid contigs and solitary cosmid clones which contain the 63 plus 22 Vϰ gene signals mentioned above comprise about 2.0 Mb. Assuming that the remaining 55 Vϰ genes are spaced at the same average distance of 24 kb, one may extrapolate to a locus size of 3.3 Mb.
Peptide‐pulsed dendritic cells induce tumoricidal cytotoxic T lymphocytes from healthy donors against stably HLA‐A*0201‐binding peptides from the Melan‐A/MART‐1 self antigen
Authors: van Elsas Andrea , van der Burg Sjoerd H. , van der Minne Carolien E. , Borghi Martina , Mourer Jacqueline S. , Melief Cornelis J. M. , Schrier Peter I. 
Published: March 2007

AbstractThe melanoma antigen Melan‐A/MART‐1 was screened for the presence of potential HLA‐A*0201‐binding cytotoxic T lymphocytes (CTL) epitopes. The immunodominant nonamer epitope AAGIGILTV demonstrated weak binding to T2 but a significant half‐life of binding to HLA‐A*0201 in contrast to the decamer EAAGIGILTV. In addition to the immunodominant CTL epitope, we describe two peptides, GILTVILGV and ALMDKSLHV, that display stable binding to HLA‐A*0201. Using cultured autologous dendritic cells pulsed with these peptides, CTL lines were induced from peripheral blood lymphocytes that displayed reactivity with HLA‐A2+, Melan‐A/MART‐1+ melanoma cells. CTL reactivity against the immunodominant epitope could be induced with the nonamer epitope alone, but not with the decamer variant. CTL clones generated from an (EAAGIGILTV + AAGIGILTV)‐induced CTL line recognize the appropriate melanoma cells and normal melanocytes. Upon further characterization of one of these CTL clones, it was found to be of surprisingly high affinity considering that it is directed against a self antigen. This study demonstrates that immunogenic peptides can be selected based on stability (half‐life) of peptide/HLA binding. In addition, cultured DC were found to efficiently induce CTL responses in vitro against such selected peptides, and some of these CTL were capable of recognizing endogenously processed antigen.
Urtica dioica agglutinin, a Vβ8.3‐specific superantigen, prevents the development of the systemic lupus erythematosus‐like pathology of MRL lpr/lpr mice
Authors: Musette Philippe , Galelli Anne , Chabre Henri , Callard Patrice , Peumans Willy , Truffa‐Bachi Paolo , Kourilsky Philippe , Gachelin Gabriel 
Published: March 2007

AbstractThe Vβ8.3‐specific superantigenic lectin Urtica dioica agglutinin (UDA) was used to delete the Vβ8.3+ T cells in MRL lpr/lpr mice. In contrast to the systemic lupus erythematosus‐like pathology which progresses with age in the phosphate‐buffered saline‐injected MRL lpr/lpr controls, UDA‐treated animals did not develop overt clinical signs of lupus and nephritis. The pathogenic T cell clones thus reside within the Vβ8.3+ T cell population, which includes an expanded T cell clone described previously. Finally, UDA alters the production of autoantibodies in a sex‐dependent manner.
Lack of oral tolerance but oral priming for contact sensitivity to dinitrofluorobenzene in major histocompatibility complex class II‐deficient mice and in CD4+ T cell‐depleted mice
Authors: Desvignes Cyril , Bour Héléne , Nicolas Jean‐François , Kaiserlian Dominique 
Published: March 2007

AbstractOral tolerance is defined by immune unresponsiveness after oral administration of soluble antigens and by antigen‐specific inhibition of peripheral immune responses induced by prior antigen feeding. The aim of this study was to investigate the implication of the major histocompatibility complex (MHC) class II presentation pathway to CD4+ T cells in oral tolerance of contact sensitivity (CS) to the hapten dinitrofluorobenzene (DNFB). We used MHC class II knockout (ABº/º) and invariant chain knockout (Iiº/º) mice, which have, respectively, a total or partial defect in class II‐restricted activation of CD4+ T cells, as well as normal C57BL/6 mice depleted of CD4+ T cells by injection of a specific antibody. Intragastric administration of DNFB prior to skin sensitization induced specific inhibition of contact sensitivity to DNFB in Aβ+/º and Ii+/º heterozygotes comparable to that observed in C57BL/6 mice. In contrast, no oral tolerance was observed in either MHC class II‐deficient Aβº/º and Iiº/º homozygote mutants or in syngeneic anti‐CD4‐depleted C57BL/6 mice. Moreover, a single oral administration of DNFB, without skin sensitization, could prime Aβº/º, Iiº/º as well as anti‐CD4‐depleted C57BL/6 mice for DNFB‐specific CS. These findings demonstrate that the class II/CD4 pathway is involved in oral tolerance manifested both as the inhibition of CS by hapten feeding prior to skin sensitization, and as immune unresponsiveness of normal mice to oral administration of hapten. Furthermore, our data provide evidence that a single oral feeding with DNFB is able to prime mice for hapten‐specific CS, provided that the class II/CD4 pathway is bypassed.
The role of CD8+ T cells in the initiation of insulin‐dependent diabetes mellitus
Authors: Wang Bo , Gonzalez Antonio , Benoist Christophe , Mathis Diane 
Published: March 2007

AbstractWhile it is generally accepted that T cells are critical for the development of diabetes in the non‐obese diabetic (NOD) mouse, the precise functions of the CD4+ and CD8+ subsets remain ill‐defined. Transfer experiments have provided evidence that CD4+ cells are the disease initiators, provoking massive mononuclear leukocyte infiltration into the pancreatic islets, while CD8+ cells play an effector role, responsible for the final destruction of islet beta cells. It was surprising, then, to find that NOD mice carrying a null mutation at the β2‐microglobulin (β2‐μ) locus, and thereby lacking major histocompatibility complex class I molecules and CD8+ T cells, developed neither insulitis nor diabetes. Here, we argue that the absence of insulitis in these animals results from their lack of CD8+ cells because islet infiltration is also absent when NOD mice are treated with an anti‐CD8 monoclonal antibody (mAb) at a young age. Interestingly, the anti‐CD8 effect is only observed when the mAb is injected during a discrete age window – 2 to 5 weeks after birth. Transfer experiments indicate that the lack of CD8+ cells during this period somehow alters the phenotype of CD4+ cells, preventing them from expressing their insulitic potential. This is not because they are generally immuno‐incompetent nor because they are generally more prone to differentiating into cells with Th2 characteristics. Given that neither the β2‐μ mutation nor anti‐CD8 treatment affect insulitis in a T cell receptor transgenic (tg) mouse strain with a CD4+ T cell repertoire highly skewed for an anti‐islet cell reactivity, the most straight‐forward interpretation of these observations is that CD8+ cells are required for effective priming and expansion of autoreactive CD4+ cells.
Differential induction of helper and killer T cells from isolated CD4+CD8+ thymocytes in suspension culture
Authors: Iwata Makoto , Kuwata Takeshi , Mukai Mutsumi , Tozawa Yuzuru , Yokoyama Minesuke 
Published: March 2007

AbstractThymocytes of T cell receptor transgenic mice with nonselecting and RAG‐2−/− backgrounds were developmentally arrested at the CD4+CD8+ stage before positive selection. These thymocytes underwent lineage commitment upon transient stimulation with a combination of ionomycin, a calcium ionophore, and phorbol 12‐myristate 13‐acetate (PMA), a protein kinase C activator, in suspension culture. The effective drug doses were limited within narrow ranges and much lower than those which induce proliferation of mature T cells. The doses corresponded to those which inhibit glucocorticoid‐induced apoptosis in these thymocytes. CD4 lineage commitment required longer duration, higher intensity of the stimulation, or both, than CD8 lineage commitment. Functional helper T cells (Th1 and Th2) were induced from the CD4 lineage‐committed cells upon secondary stimulation with a combination of ionomycin and PMA followed by lymphokine treatment. Cytotoxic T cells were induced from the CD8 lineage‐committed cells upon incubation with concanavalin A and irradiated splenic dendritic cells, but not with the combination of ionomycin and PMA. These results indicate that positive selection is mimicked by the pharmacological stimulation in the absence of other cell types, but that final maturation of CD8 T cells may require a different signal.
Severe combined immunodeficiency due to defective binding of the nuclear factor of activated T cells in T lymphocytes of two male siblings
Authors: Feske Stefan , Müller Judith M. , Graf Daniel , Kroczek Richard A. , Dräger Ruth , Niemeyer Charlotte , Baeuerle Patrick A. , Peter Hans‐Hartmut , Schlesier Michael 
Published: March 2007

AbstractPeripheral blood lymphocytes (PBL) and alloreactive T cell lines of two male infants born to consanguinous parents and presenting with severe combined immunodeficiency (SCID) showed a pronounced deficiency in T cell activation. Although phenotypically normal, the proliferative response of the childrens' T cells was strongly reduced but could be improved by the addition of interleukin‐2 (IL‐2). Furthermore both childrens'T cells were unable to produce the cytokines IL‐2, interferon‐γ (IFN‐γ), IL‐4 and tumor necrosis factor‐α (TNF‐α). This multiple cytokine production deficiency could not be restored by IL‐2 or co‐stimulatory signals provided by antigen‐presenting cells (APC). Moreover, mRNA for IL‐2 and IFN‐γ could not be detected. In contrast, expression of the activation‐dependent cell surface markers CD25 and CD69 was within normal limits. To determine whether the functional defect of the patients' T cells was due to the absence or abnormal binding of transcription factors involved in cytokine gene expression, electrophoretic mobility shift assays were used to examine the DNA binding of AP‐1, Oct, CREB, SP1, NF‐ϰB and the nuclear factor of activated T cells (NF‐AT) to their respective response elements in the promoter of the IL‐2 gene. Whereas AP‐1, NF‐ϰB, Oct, CREB and SP1 displayed normal binding activities in nuclear extracts, the binding of NF‐AT to its IL‐2 promoter response element was barely detectable both before and after T cell stimulation. Our results strongly suggest that this NF‐AT/DNA binding defect is responsible for the multiple cytokine deficiency and the SCID phenotype observed in the two infant brothers.
Regulation of B cell growth and differentiation via CD21 and CD40
Authors: Axcrona Karol , Gray David , Leanderson Tomas 
Published: March 2007

AbstractStimulation in vitro of murine splenic B cells by lipopolysaccharide, anti‐ϰ Sepharose, anti‐CD40 or allo‐reactive T helper cells all up‐regulated CD21 and CD23 surface expression. Neither anti‐CD21 nor anti‐CD23 antibodies induced B cell growth or differentiation when added in soluble form or coupled to Sepharose. However, anti‐CD40‐stimulated B cells showed increased proliferation in the presence of anti‐CD21 antibodies coupled to Sepharose; co‐stimulation via CD21 also induced differentiation to immunoglobulin secretion in a fraction of anti‐CD40‐stimulated B cells. Furthermore, anti‐CD40 antibodies inhibited differentiation to immunoglobulin secretion induced by lipopolysaccharide and, hence, appears to be a dominant negative signal for B cell differentiation.
Correlation between immune maturation and idiotypic network recognition
Authors: Lange Hans , Solterbeck Meika , Berek Claudia , Lemke Hilmar 
Published: March 2007

AbstractThe maturation of T‐dependent humoral immune responses is mediated by somatic mutations. Antigen selection is one mechanism for the activation of B cell clones which express antibodies with progressively increased affinity and which are derived as somatic variants from germ‐line‐encoded genes. However, the emergence of B cell clones secreting rather low‐affinity antibodies and the shift to alternative germ‐line V region gene combinations during secondary and tertiary responses cannot be explained by antigen selection. It has been considered that idiotypic suppression may favor this clonal shift. Such an involvement would require that idiotypic recognition in the syngeneic host must be highly restricted to private idiotopes of each clone sequentially activated during immune maturation. To test this possibility, we produced 19 syngeneic anti‐idiotypic antibodies to the germ‐line‐encoded major Ox1 idiotype (IgM‐IdOx1 H11.5) of the anti‐2‐phenyl‐oxazolone (phOx) immune response in BALB/c mice. The fine specificity of these anti‐IdOx1 was tested with a set of anti‐phOx monoclonal antibodies, representing the first steps of maturation. About half of the anti‐IdOx1 showed almost no reactivity with the IdOx1 after the switch to IgG and none of the anti‐IdOx1 reacted with anti‐phOx antibodies which carried a glycine or histidine instead of arginine as the middle amino acid of the D region. These observations suggest a strong correlation between immune maturation and the idiotypic network. A model is presented in which idiotypic suppression may function as a driving force for diversification and maturation of the antigen‐induced immune response.
Complexity of the mouse gut T cell immune system: Identification of two distinct natural killer T cell intraepithelial lineages
Authors: Guy‐Grand Delphine , Cuénod‐Jabri Bana , Malassis‐Seris Michèle , Selz Françoise , Vassalli Pierre 
Published: March 2007

AbstractGut thymo‐dependent (CD8α+β+ or CD4+) or ‐independent (CD8α+β−) intraepithelial lymphocytes (IEL) mediate cytotoxicity following T cell receptor (TCR)‐CD3 signaling, but only TCRγδ+ and αβ+ thymo‐independent IEL show cytotoxicity of natural killer (NK) and antibody‐dependent cell‐mediated cytotoxicity types. Moreover, TCRαβ+ and γδ+ thymo‐independent IEL express NK receptors, and may therefore be referred to as NK‐TIEL. NK‐TIEL cytotoxicity is mediated through perforin, Fas, or both pathways. In contrast to that of other NK cells, this cytotoxicity is not negatively regulated by signals delivered through the recognition of major histocompatibility complex class I molecules. Thus, gut IEL include T cell subsets with unique specificities and functions, ontogenically distinct from other T cell lineages, which may increase the antigenic repertoire diversity of the immune system participating in the defense of the epithelial barrier.
Abnormal production of T helper 2 cytokines interleukin‐4 and interleukin‐5 by T cells from newborns with atopic parents
Authors: Piccinni Marie‐Pierre , Beloni Lucio , Giannarini Loretta , Livi Claudia , Scarselli Gianfranco , Romagnani Sergio , Maggi Enrico 
Published: March 2007

AbstractT cell clones were generated from umbelical cord blood lymphocytes (UCBL) of nine newborns with atopic or nonatopic parents and their cytokine secretion profile was assessed. Both phytohemagglutinin‐induced and Dermatophagoides pteronyssinus‐spetific T cell clones from newborns with atopic parents exhibited an enhanced ability to produce the Th2 cytokines interleukin (IL)‐4 and IL‐5, compared to T cell clones from newborns with nonatopic parents. In contrast, the ability to produce interferon‐γ by UCBL from the two groups of newborns was not different. Of the five children who could be followed up to 3 years after birth, four with atopic parents developed clinical and/or biological atopic manifestations, whereas one without atopic parents did not. Thus, the pronounced production of IL‐4 and IL‐5 by UCBL not only appears to be related to the atopic status of parents, but also associates with the subsequent development of atopy in childhood.
L1 adhesion molecule on human lymphocytes and monocytes: expression and involvement in binding to αvβ3 integrin
Authors: Ebeling Olaf , Duczmal Andreas , Aigner Silke , Geiger Claudia , Schöllhammer Sandra , Kemshead John T. , Möller Peter , Schwartz‐Albiez Reinhard , Altevogt Peter 
Published: March 2007

AbstractThe L1 adhesion molecule is a member of the immunoglobulin (Ig) superfamily initially identified in the nervous system which contains six Ig‐like domains. Besides the known L1‐L1 homotypic interaction, L1 was recently shown to bind to very late antigen (VLA)‐5 in the mouse and αvβ3 in the human. The sixth Ig domain is critical for this function. We now demonstrate that human CD4+ peripheral blood T lymphocytes, monocytes and B lymphocytes, but not CD8+ T lymphocytes, express L1. When compared to the expression of CD31, another ligand for αvβ3 on T lymphocytes, only a small proportion of cells were CD31+L1+ double positive. L1 was also detected on the surface of human monocytic and lymphoid tumor lines and was shown to have a molecular mass of ∼220 kDa, similar to the molecule present on neuroblastoma cells. The function of the sixth Ig domain of human L1 as an integrin ligand was also investigated. Using an RGD‐containing peptide derived from the sixth Ig domain as well as a fusion protein of the sixth Ig domain of L1 and the Fc portion of human IgG1 (6.L1‐Fc), we demonstrated the binding of human MED‐B1 (αvβ3hi, α5β1lo) tumor cells and this binding was blocked by αv‐specific mAb. In contrast, human Nalm‐6 cells (αvβ3lo, α5β1hi) did not bind to the 6.L1‐Fc fusion protein. MED‐B1 cells could also be stained with the 6.L1‐Fc fusion protein. Our results suggest that human L1 binds predominantly to αvβ3 and that its presence on leukocytes could be important for adhesion and migration.
Tumor cells expressing a recall antigen are powerful cancer vaccines
Authors: Schweighoffer Tamás 
Published: March 2007

AbstractTumor cells were engineered to express a specific recall antigen molecule to serve as a target for the host's existing memory response, and then used as immunogens as a novel form of cancer vaccine. As recall antigen, the efficiently expressible hybrid protein Heat1 was employed, that contains an antigenic fragment of the Mycobacterium bovis 65‐kDa heat shock protein (hsp65), and thus can be recognized in mice immunized with live Bacillus Calmette‐Guérin (BCG) or its derivatives. Mouse M‐3 melanoma cells were transfected to express Heat1, irradiated, and used as anti‐melanoma vaccines. Vaccination elicited anti‐tumor immunity in mice, i.e. a subsequent challenge with the parental wild‐type M‐3 melanoma cells was rejected. Successful vaccination was dependent on the correct recognition of the recall antigen, since vaccination failed to prevent outgrowth of the challenge in mice possessing no memory response against the recall antigen. The results indicate that expression of a recall antigen can turn tumor cells into powerful vaccines. By using the Heat1 protein or other appropriate antigens, this general concept may be applied for human therapy.
Amino acid substitutions at position 97 in HLA‐A2 segregate cytolysis from cytokine release in MART‐1/Melan‐A peptide AAGIGILTV‐specific cytotoxic T lymphocytes
Authors: Maeurer Markus J. , Chan Huei‐Wie , Karbach Julia , Salter Russell D. , Knuth Alex , Lotze Michael T. , Storkus Walter J. 
Published: March 2007

AbstractCD8+ T lymphocytes recognize antigenic peptides presented by major histocompatibility complex (MHC) class I molecules. Individual peptide termini appear to be fixed at the C‐ and N‐terminal ends. In contrast, central peptide side chains residues may point in different directions and exhibit limited flexibility, dependent on the MHC class I structural variation. For instance, position 97 in HLA‐A201 has been shown to shift individual peptide species into different coordinations, one oriented towards the peptide N terminus, or more towards the C‐terminal end. The conformational shape of such non‐anchor peptide residues may affect the affinity of MHC/peptide / TCR interaction, resulting in quantitative, or qualitative different T cell effector functions. To characterize the impact of different amino acid residues occupying position 97 in HLA‐A2 on peptide binding and presentation to CTL, we generated a panel of mutated HLA‐A2 molecules containing either M, K, T, V, G, Q, W, P or H at position 97. The HLA‐A0201 presented melanoma‐associated MART‐1/Melan‐A derived peptide AAGIGILTV was employed to assess the impact of such position‐97 mutations on HLA‐A2 in peptide binding measured in an HLA‐A2 reconstitution assay and presentation to AAGIGILTV‐specific polyclonal or clonal T lymphocytes as measured by cytotoxicity, or interferon (IFN)‐γ and granulocyte/macrophage colony‐stimulating factor (GM‐CSF) secretion. The high‐affinity AAGIGILTV peptide bound to all position‐97 mutants, albeit with differential efficiencies, and elicited specific release of IFN‐γ and GM‐CSF by CTL. CTL responses were triggered only by the HLA‐A2 wild type, by HLA‐A2‐H97 (histidine position 97 mutant), and HLA‐A2‐W97. The HLA‐A2‐M97 presenting molecule elicited enhanced cytokine release and CTL effector functions by polyclonal and by clonal effector T cells. These results indicate that MHC class I‐bound peptides can trigger specific cytokine release by effector T cells independently of their ability to induce cytolysis. We conclude that relatively minor changes in the MHC class I peptide binding groove, including substitutions at position 97, can affect recognition by antigen‐specific T cells. Mutant MHC class I molecules, such as those described here, may act as partial peptide antagonists and could be usefol for inducing T lymphocytes with qualitatively different effector functions.
Suppression of adjuvant arthritis in rats by induction of oral tolerance to mycobacterial 65‐kDa heat shock protein
Authors: Haque M. Azizul , Yoshino Shin , Inada Shigeyasu , Nomaguchi Hiroko , Tokunaga Osamu , Kohashi Osamu 
Published: March 2007

AbstractOral administration of mycobacterial 65‐kDa heat shock protein (HSP) given daily for 5 days prior to immunization with Mycobacterium tuberculosis (Mt) suppressed the development of adjuvant arthritis (AA) in rats. AA was significantly suppressed by 30 and 300 μg HSP, and variably by 0.3, 3 μg or 1 mg. Histological analysis of joint samples obtained from control and test rats confirmed the suppression of AA in the fed group. Feeding Mt or hen egg lysozyme (HEL) failed to affect AA, indicating that the suppression was HSP specific. The oral administration of 30 μg HSP decreased both delayed‐type hypersensitivity (DTH) reactions and proliferative responses to HSP and Mt. In addition, the proliferation of lymph node cells (LNC) from Mt‐sensitized rats was inhibited by the addition of spleen cells (SPC) from HSP‐fed animals, possibly by the secretion of transforming growth factor (TGF)‐β. Spleen cells obtained from tolerized donors were capable of transferring the tolerance to naive recipients. These results demonstrate that feeding HSP is an effective way to suppress AA and that the suppression of AA may be mediated by regulatory T cells generated following oral administration of mycobacterial 65‐kDa HSP.