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  • 1
    Online Resource
    Online Resource
    RESTRICTION OF GENE EXPRESSION IN B LYMPHOCYTES AND THEIR PROGENY
    Rockefeller University Press ; 1974
    In:  The Journal of Experimental Medicine Vol. 140, No. 2 ( 1974-08-01), p. 452-469
    Details
    In: The Journal of Experimental Medicine, Rockefeller University Press, Vol. 140, No. 2 ( 1974-08-01), p. 452-469
    Abstract: To determine whether or not B lymphocytes are committed to the synthesis of a single immunoglobulin heavy chain isotype during their differentiation into plasma cells, rabbit lymph node and Peyer's patch cells were separated into populations with and without membrane IgM, using a fluorescence-activated cell sorter (FACS). The potential of the µ-bearing (µ+) and non-µ-bearing (µ-) cells to give rise to plasma cells both in vivo after transfer into irradiated recipients and in vitro in the presence of pokeweed mitogen was assessed by immunofluorescence techniques, and the relative proportions of the cytoplasmic Ig-stained cells (CSC) synthesizing each class of heavy chains were determined. Most of the CSC arising in vitro from µ-bearing lymph node and Peyer's patch cells contained IgM; all IgM CSC appeared to be derived from µ+ cells. Peyer's patch lymphocytes, however, did not generate IgM CSC after cell transfer and thus may be functionally different from lymph node µ+ cells. It was found also that nearly all of the many IgA CSC generated by Peyer's patch lymphocytes either in culture or after transfer were derived from µ- cells. Further fractionation of these µ- cells with the FACS after they had been membrane stained with anti-b locus allotype reagents revealed that the precursors of IgA CSC belong to a minor population of cells which do have b locus light chain determinants on their membranes, although they do not have detectable µ-chains. These cells are not found in lymph nodes. Although the majority of Peyer's patch and lymph node cells were found to be precommitted to the synthesis of a single heavy chain isotype, a small proportion of cells may not be similarly restricted. Some of the CSC with membrane IgM were found to contain cytoplasmic IgA or IgG. In addition, µ+ populations did give rise to low numbers of IgA and IgG CSC. The implications of these results, obtained under experimental conditions, on the normal differentiation of B lymphocytes in situ are discussed.
    Type of Medium: Online Resource
    ISSN: 1540-9538 , 0022-1007
    URL: Article
    DOI: 10.1084/jem.140.2.452
    RVK:
    XA 10000
    Language: English
    Publisher: Rockefeller University Press
    Publication Date: 1974
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  • 2
    Online Resource
    Online Resource
    Evidence That the Autoimmune Antigen Myelin Basic Protein (MBP) Ac1-9 Binds Towards One End of the Major Histocompatibility Complex (MHC) Cleft
    Rockefeller University Press ; 1998
    In:  The Journal of Experimental Medicine Vol. 187, No. 9 ( 1998-05-04), p. 1505-1516
    Details
    In: The Journal of Experimental Medicine, Rockefeller University Press, Vol. 187, No. 9 ( 1998-05-04), p. 1505-1516
    Abstract: The NH2-terminal peptide of myelin basic protein (MBP) bound to the class II major histocompatibility complex (MHC) protein I-Au is an immunodominant epitope in experimental autoimmune encephalomyelitis, a murine model of multiple sclerosis. However, the MBP–I-Au complex is very unstable. To investigate this, we performed site-directed mutagenesis of the I-Au MHC protein and the MBP peptide. Biochemical, T cell activation, and molecular modeling studies of mutant complexes demonstrate that the MBP peptide's key residue for MHC binding, lysine 4, is buried in the P6 pocket of I-Au, which is predominantly hydrophobic. This implies that the MBP–I-Au complex differs from more stable complexes in two respects: (a) the peptide leaves the NH2-terminal region of the MHC peptide-binding cleft unoccupied; (b) the peptide is not anchored by typical favorable interactions between peptide side chains and MHC pockets. To test these hypotheses, a modified MBP peptide was designed based on molecular modeling, with the aim of producing strong I-Au binding. Extension of the NH2 terminus of MBP with six amino acids from the ova peptide, and replacement of the lysine side chain in the P6 pocket with an aromatic anchor, results in & gt;1,000-fold increased binding stability. These results provide an explanation for the unusual peptide–MHC-binding kinetics of MBP, and should facilitate an understanding of why mice are not tolerant to this self-peptide– MHC complex.
    Type of Medium: Online Resource
    ISSN: 0022-1007 , 1540-9538
    URL: Article
    DOI: 10.1084/jem.187.9.1505
    RVK:
    XA 10000
    Language: English
    Publisher: Rockefeller University Press
    Publication Date: 1998
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  • 3
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    Online Resource
    Novel Genetic Regulation of  T Helper 1 (Th1)/Th2 Cytokine Production and Encephalitogenicity in Inbred Mouse Strains
    Rockefeller University Press ; 1997
    In:  The Journal of Experimental Medicine Vol. 185, No. 3 ( 1997-02-03), p. 439-452
    Details
    In: The Journal of Experimental Medicine, Rockefeller University Press, Vol. 185, No. 3 ( 1997-02-03), p. 439-452
    Abstract: Development of T helper cell (Th)1 or Th2 cytokine responses is essential for effector and regulatory functions of T helper cells. We have compared cytokine profiles of myelin basic protein (MBP) Ac1-16 peptide-specific T helper cells from inbred mouse strains expressing identical k haplotype-derived MHC class II molecules B10.A and B10.BR. B10.BR T cell lines (TCL) produced Th1 cytokines (including high levels of TNF-α) and induced experimental autoimmune encephalomyelitis after adoptive transfer. In contrast, B10.A TCL produced Th2 cytokines (including low levels of TNF-α) and were poorly encephalitogenic. The contributions of the genetic origin of the T cells and the APC were explored. Serial restimulations of the B10.BR TCL with B10.A or (B10.A × B10.BR) F1 splenic antigen presenting cells (APC) during the establishment of TCL markedly reduced both Th1 cytokine production and encephalitogenicity. In addition, a single restimulation with B10.A splenic APC reduced IFN-γ and TNF-α production by established Th1 MBP-specific Ak-restricted B10.BR TCL and by a Th1 KLH-specific, Ek-restricted B10.BR T cell clone. These studies suggest that B10.A and B10.BR APC differ in their ability to stimulate IFN-γ and TNF-α production by mature Th1 cells and also influence their Th1/Th2 commitment in vivo. The nature of the downregulatory activity of B10.A APC on IFN-γ and TNF-α production was explored. 2-hour supernatants from antigen-activated B10.A APC/TCL cultures or from B10.A APC activated by LPS had the same inhibitory effects on IFN-γ and TNF-α production by B10.BR TCL. The downregulatory effects of B10.A APC are independent of TNF-α, IL-4, IL-10, IL-12p40, IFN-γ, IL-13, TGF-β, and PGE2. Thus, genetic difference(s) between B10.A and B10.BR APC appear(s) to control the production or activity of a novel soluble cytokine regulatory factor that influences Th1/Th2 commitment and controls production of IFN-γ and TNF-α by mature Th1 cells.
    Type of Medium: Online Resource
    ISSN: 0022-1007 , 1540-9538
    URL: Article
    DOI: 10.1084/jem.185.3.439
    RVK:
    XA 10000
    Language: English
    Publisher: Rockefeller University Press
    Publication Date: 1997
    detail.hit.zdb_id: 1477240-1
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  • 4
    Online Resource
    Online Resource
    RESTRICTION OF GENE EXPRESSION IN B LYMPHOCYTES AND THEIR PROGENY
    Rockefeller University Press ; 1974
    In:  The Journal of Experimental Medicine Vol. 140, No. 4 ( 1974-10-01), p. 966-976
    Details
    In: The Journal of Experimental Medicine, Rockefeller University Press, Vol. 140, No. 4 ( 1974-10-01), p. 966-976
    Abstract: Fluorescent antibody staining with antibodies to the f and g locus allotype markers present on rabbit α-chains revealed that the α-chain is the heavy chain on the Peyer's patch lymphocytes which previously had been shown to be the precursors of IgA-producing plasma cells. In addition, lymphocytes which had been stripped of membrane Ig with pronase and then cultured overnight to allow the sole expression of endogenous membrane Ig were found to have either the µ-chain or the α-chain on their membranes, but not both. These results suggest that most lymphocytes are restricted to the synthesis of one class of heavy chains at a time and that the commitment to synthesizing that particular heavy chain is maintained during the differentiation of lymphocytes into plasma cells. The proportion of lymphocytes with membrane α-chains is higher in the Peyer's patch and appendix, two gut-associated lymphoid tissues (GALT), than in other lymphoid tissues. Since the GALT are enriched sources of precursors for IgA-producing plasma cells compared to nongut-associated tissues, the presence of cells bearing membrane α-chains correlates well with the relative abilities of these tissues to generate IgA plasma cells.
    Type of Medium: Online Resource
    ISSN: 1540-9538 , 0022-1007
    URL: Article
    DOI: 10.1084/jem.140.4.966
    RVK:
    XA 10000
    Language: English
    Publisher: Rockefeller University Press
    Publication Date: 1974
    detail.hit.zdb_id: 1477240-1
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  • 5
    Online Resource
    Online Resource
    RESTRICTION OF GENE EXPRESSION IN B LYMPHOCYTES AND THEIR PROGENY
    Rockefeller University Press ; 1974
    In:  The Journal of Experimental Medicine Vol. 139, No. 3 ( 1974-03-01), p. 581-599
    Details
    In: The Journal of Experimental Medicine, Rockefeller University Press, Vol. 139, No. 3 ( 1974-03-01), p. 581-599
    Abstract: Lymphocytes from b5/b9 rabbits were stained in suspension with fluorescent antiallotype antibody reagents to selectively label with fluorescent molecules those cells bearing membrane immunoglobulin (Ig) of the b5 or b9 allotype. After staining, the cells were separated by the fluorescence-activated cell sorter into populations markedly enriched in cells bearing b5 or b9 membrane Ig or totally depleted of cells with detectable membrane Ig. The potential of these separated cells to give rise to Ig-synthesizing plasma cells either in vivo after transfer into irradiated recipients or in vitro during culture in the presence of phytohemagglutinin or pokeweed mitogen was assessed by immunofluorescence. The relative proportion of b5 and b9 cytoplasmic Ig-stained cells (CSC) arising from the separated cells was determined to test directly whether B lymphocytes and their progeny are committed to the synthesis of Ig of one allotype. It was found that b5- and b9-bearing cells gave rise almost exclusively to b5- and b9-producing plasma cells, respectively, in both the in vivo and in vitro assay systems. Most of these CSC were probably not derived from previously existing CSC but arose as the result of the differentiation of lymphocytes with membrane Ig. When cell populations totally depleted of Ig-bearing lymphocytes were cultured, very few CSC were found, indicating that the majority of immediate precursors of CSC have membrane Ig. These results suggest that individual B cell clones are phenotypically restricted to the expression of immunoglobulin genes on one chromosome; the significance of this clonal allelic exclusion is discussed.
    Type of Medium: Online Resource
    ISSN: 1540-9538 , 0022-1007
    URL: Article
    DOI: 10.1084/jem.139.3.581
    RVK:
    XA 10000
    Language: English
    Publisher: Rockefeller University Press
    Publication Date: 1974
    detail.hit.zdb_id: 1477240-1
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  • 6
    Online Resource
    Online Resource
    Nucleoside-modified mRNA vaccines induce potent T follicular helper and germinal center B cell responses
    Rockefeller University Press ; 2018
    In:  Journal of Experimental Medicine Vol. 215, No. 6 ( 2018-06-04), p. 1571-1588
    Details
    In: Journal of Experimental Medicine, Rockefeller University Press, Vol. 215, No. 6 ( 2018-06-04), p. 1571-1588
    Abstract: T follicular helper (Tfh) cells are required to develop germinal center (GC) responses and drive immunoglobulin class switch, affinity maturation, and long-term B cell memory. In this study, we characterize a recently developed vaccine platform, nucleoside-modified, purified mRNA encapsulated in lipid nanoparticles (mRNA-LNPs), that induces high levels of Tfh and GC B cells. Intradermal vaccination with nucleoside-modified mRNA-LNPs encoding various viral surface antigens elicited polyfunctional, antigen-specific, CD4+ T cell responses and potent neutralizing antibody responses in mice and nonhuman primates. Importantly, the strong antigen-specific Tfh cell response and high numbers of GC B cells and plasma cells were associated with long-lived and high-affinity neutralizing antibodies and durable protection. Comparative studies demonstrated that nucleoside-modified mRNA-LNP vaccines outperformed adjuvanted protein and inactivated virus vaccines and pathogen infection. The incorporation of noninflammatory, modified nucleosides in the mRNA is required for the production of large amounts of antigen and for robust immune responses.
    Type of Medium: Online Resource
    ISSN: 0022-1007 , 1540-9538
    URL: Article
    DOI: 10.1084/jem.20171450
    RVK:
    XA 10000
    Language: English
    Publisher: Rockefeller University Press
    Publication Date: 2018
    detail.hit.zdb_id: 1477240-1
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