scholarly journals Inhibition of Interleukin 7 Receptor Signaling by Antigen Receptor Assembly

2000 ◽  
Vol 191 (4) ◽  
pp. 737-742 ◽  
Author(s):  
Fiona M. Smart ◽  
Ashok R. Venkitaraman
Keyword(s):  
Heavy Chain ◽  
B Lymphocyte ◽  
Antigen Receptor ◽  
Cytoplasmic Domain ◽  
Chain Gene ◽  
Inhibition Of Proliferation ◽  
Light Chain Gene ◽  
Murine Bone Marrow ◽  
Interleukin 7 ◽  
Receptor Assembly

After the productive rearrangement of immunoglobulin (Ig) heavy chain genes, precursor (pre-)B lymphocytes undergo a limited number of cell divisions in response to interleukin (IL)-7. Here, we present evidence that this phase of IL-7–dependent expansion is constrained by an inhibitory signal initiated by antigen receptor assembly. A line of pre-B cells from normal murine bone marrow that expresses a μ heavy chain with a D-proximal VH7183.2 region divides continuously in IL-7. IL-7 responsiveness ceases upon differentiation to the μ1, κ1 stage, despite continuing expression of the IL-7 receptor (IL-7R), suggesting that antigen receptor assembly inhibits IL-7 responsiveness. This is confirmed by introduction of a rearranged λ light chain gene, which inhibits proliferative signaling through the IL-7R. Inhibition is specific to the IL-7R, because it is overcome by replacement of the IL-7R cytoplasmic domain with corresponding sequences from the closely related IL-2Rβ chain. Alteration of a single tyrosine residue, Tyr410, in the IL-7R cytoplasmic domain to phenylalanine also prevents the inhibition of proliferation after antigen receptor assembly. Thus, the loss of IL-7 responsiveness after antigen receptor assembly may be mediated through the recruitment of an inhibitory molecule to this residue. Our findings identify a novel mechanism that limits cytokine-dependent proliferation during B lymphopoiesis. This mechanism may be essential for the proper regulation of peripheral B lymphocyte numbers.

Pi, a pre-B-cell-specific enhancer element in the immunoglobulin heavy-chain enhancer

1993 ◽  
Vol 13 (10) ◽  
pp. 5957-5969
Author(s):  
T A Libermann ◽  
D Baltimore
Keyword(s):  
B Cell ◽  
Heavy Chain ◽  
Mutational Analysis ◽  
Protein S ◽  
Immunoglobulin Heavy Chain ◽  
Chain Gene ◽  
Cell Stage ◽  
Enhancer Activity ◽  
Enhancer Element ◽  
Light Chain Gene

We have identified a new immunoglobulin heavy-chain enhancer element, designated pi, between the microE2 and microE3 elements. The pi enhancer element is transcriptionally active primarily during early stages of B-cell development but becomes virtually inactive during B-cell maturation at about the stage of immunoglobulin kappa light-chain gene rearrangement. Mutational analysis suggests that the pi element is crucial for immunoglobulin heavy-chain enhancer activity at the pre-B-cell stage but is almost irrelevant for enhancer activity at the mature B-cell or plasma-cell stage. The activity of the pi enhancer element correlates with the presence of an apparently pre-B-cell-specific protein-DNA complex. The similarity of the pi site to recognition sequences for members of the ets gene family suggests that the protein(s) interacting with the pi site most likely are ets-related transcription factors.

Promoter Element for Transcription of Unrearranged T-Cell Receptor β-Chain Gene in Pro-T Cells

Blood ◽  
1999 ◽  
Vol 93 (9) ◽  
pp. 3017-3025 ◽  
Author(s):  
Raymond T. Doty ◽  
Dong Xia ◽  
Suzanne P. Nguyen ◽  
Tanya R. Hathaway ◽  
Dennis M. Willerford
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
B Lymphocyte ◽  
Developmental Regulation ◽  
Antigen Receptor ◽  
Cell Receptor ◽  
Chain Gene ◽  
Germline Transcription ◽  
Lineage Specificity ◽  
T Cell Lines

Abstract The hallmark of T- and B-lymphocyte development is the rearrangement of variable (V), diversity (D), and joining (J) segments of T-cell receptor (TCR) and immunoglobulin (Ig) genes to generate a diverse repertoire of antigen receptor specificities in the immune system. The process of V(D)J recombination is shared in the rearrangement of all seven antigen receptor genes and is controlled by changes in chromatin structure, which regulate accessibility to the recombinase apparatus in a lineage- and stage-specific manner. These chromatin changes are linked to transcription of the locus in its unrearranged (germline) configuration. To understand how germline transcription of the TCRβ-chain gene is regulated, we determined the structure of germline transcripts initiating near the Dβ1 segment and identified a promoter within this region. The Dβ1 promoter is active in the presence of the TCRβ enhancer (Eβ), and in this context, exhibits preferential activity in pro-T versus mature T-cell lines, as well as T- versus B-lineage specificity. These studies provide insight into the developmental regulation of TCRβ germline transcription, one of the earliest steps in T-cell differentiation.

scholarly journals Genetic and Immunological Properties of Phage-Displayed Human Anti-Rh(D) Antibodies: Implications for Rh(D) Epitope Topology

Blood ◽  
1998 ◽  
Vol 91 (8) ◽  
pp. 3066-3078 ◽  
Author(s):  
Tylis Y. Chang ◽  
Don L. Siegel
Keyword(s):  
Heavy Chain ◽  
Relevant Information ◽  
Peripheral Blood Lymphocytes ◽  
Antibody Binding ◽  
Light Chains ◽  
Chain Gene ◽  
Light Chain Gene ◽  
Heavy Chains ◽  
Epitope Specificity ◽  
Gene Usage

Understanding anti-Rh(D) antibodies on a molecular level would facilitate the genetic analysis of the human immune response to Rh(D), lead to the design of therapeutically useful reagents that modulate antibody binding, and provide relevant information regarding the structural organization of Rh(D) epitopes. Previously, we described a Fab/phage display-based method for producing a large array of anti-Rh(D) antibodies from the peripheral blood lymphocytes of a single alloimmunized donor. In the current study, we present a detailed analysis of 83 randomly selected clones. Sequence analysis showed the presence of 28 unique γ1 heavy chain and 41 unique light chain gene segments. These paired to produce 53 unique Fabs that had specificity for at least half of the major Rh(D) epitopes. Surprisingly, despite this diversity, only 4 closely related heavy chain germline genes were used (VH3-30, VH3-30.3, VH3-33, and VH3-21). Similarly, nearly all Vκ light chains (15/18) were derived from one germline gene (DPK9). λ light chains showed a more diverse VL gene usage, but all (23/23) used the identical Jλ2 gene. Several Fabs that differed in epitope specificity used identical heavy chains but different light chains. In particular, 2 such clones differed by only 3 residues, which resulted in a change from epD2 to epD3 specificity. These results suggest a model in which footprints of anti-Rh(D) antibodies are essentially identical to one another, and Rh(D) epitopes, as classically defined by panels of Rh(D) variant cells, are not discrete entities. Furthermore, these data imply that the epitope specificity of an anti-Rh(D) antibody can change during the course of somatic mutation. From a clinical perspective, this process, which we term epitope migration, has significance for the design of agents that modulate antibody production and for the creation of mimetics that block antibody binding in the settings of transfusion reactions and hemolytic disease of the newborn.

scholarly journals Pan/E2A expression precedes immunoglobulin heavy-chain expression during B lymphopoiesis in nontransformed cells, and Pan/E2A proteins are not detected in myeloid cells.

1994 ◽  
Vol 14 (6) ◽  
pp. 4087-4096 ◽  
Author(s):  
Y Jacobs ◽  
X Q Xin ◽  
K Dorshkind ◽  
C Nelson
Keyword(s):  
B Cell ◽  
Cell Line ◽  
Heavy Chain ◽  
B Lymphocyte ◽  
Myeloid Cells ◽  
Immunoglobulin Heavy Chain ◽  
Cell Development ◽  
B Cell Development ◽  
Chain Gene ◽  
Enhancer Element

A newly developed rat long-term bone marrow culture system was used to study the role of Pan/E2A basic helix-loop-helix transcription factors during B-cell development. In this system, B-lymphocyte progenitors actively differentiate into mature B cells. Monoclonal (Yae) and polyclonal (anti-Pan) antibodies were employed to characterize the expression of Pan proteins by Western blot assay during hematopoiesis and to examine the components of immunoglobulin heavy-chain gene enhancer element-binding species by electrophoretic mobility shift assay. During B-cell development, the appearance of Pan/E2A proteins preceded the expression of immunoglobulin heavy-chain protein. A Pan-containing immunoglobulin heavy-chain enhancer element (mu E5)-binding species (BCF1), composed of immunoreactive Pan-1/E47 but not Pan-2/E12, was observed concomitantly with the detection of Pan/E2A proteins. In addition to BCF1, other mu E5-binding species were detected which were not recognized by the Yae antibody. Two of these species were present in primary B-lymphocyte and myeloid cultures and were recognized by an anti-upstream stimulatory factor antiserum. Although Pan/E2A proteins have been proposed to be ubiquitous, Pan/E2A proteins were not detected in primary myeloid cultures composed mainly of granulocytes and macrophages or in the macrophage cell line J774. The absence of Pan/E2A proteins in differentiated myeloid cells correlated with low steady-state levels of Pan/E2A RNA. However, Pan/E2A proteins were present in a promyeloid cell line, 32DCL3, suggesting that extinction of Pan/E2A expression may play a role in myelopoiesis.

scholarly journals Identification of an octamer-binding site in the human kappa light-chain enhancer.

1990 ◽  
Vol 10 (7) ◽  
pp. 3843-3846 ◽  
Author(s):  
K Nelms ◽  
B Van Ness
Keyword(s):  
Binding Site ◽  
Heavy Chain ◽  
Light Chain ◽  
Tissue Specificity ◽  
Chain Gene ◽  
Gene Promoters ◽  
Kappa Light Chain ◽  
Light Chain Gene ◽  
Gene Enhancer ◽  
Light Chain Enhancer

Octamer motifs contribute to the function and tissue specificity of immunoglobulin heavy- and light-chain gene promoters and the heavy-chain enhancer. A variant octamer-binding site within a conserved region of the human kappa light-chain gene enhancer which contributes to the function of this enhancer has been identified.

scholarly journals Immunoglobulin gene rearrangements and expression in diffuse histiocytic lymphomas reveal cellular lineage, molecular defects, and sites of chromosomal translocation

Blood ◽  
1986 ◽  
Vol 67 (2) ◽  
pp. 391-397 ◽  
Author(s):  
KA Siminovitch ◽  
JP Jensen ◽  
AL Epstein ◽  
SJ Korsmeyer
Keyword(s):  
B Cell ◽  
Cell Line ◽  
Heavy Chain ◽  
Light Chain ◽  
Cell Lineage ◽  
Chromosomal Translocation ◽  
Chain Gene ◽  
Gene Rearrangements ◽  
Immunoglobulin Gene ◽  
Light Chain Gene

Abstract We have examined the immunoglobulin gene configurations in cell lines from eight patients with diffuse histiocytic lymphoma in order to establish the cellular lineage and stage of differentiation of these lymphomas. The presence of heavy and light chain gene rearrangements as well as heavy chain class switching in seven cells placed these tumors within the B cell lineage. In contrast, one cell (SU-DHL-1), which lacks B cell-restricted surface antigens, retained germline heavy and light chain loci, indicating that it may represent a true histiocyte or uncommitted cell. Truncated RNAs for both the heavy and light chain immunoglobulins were responsible for the lack of surface immunoglobulin in the SU-DHL-2 cell line. Another cell line (SU-DHL-6), which possesses a t(14;18)(q32;q21) translocation, demonstrated an unexpected recombination within its heavy chain gene locus that may be the interchromosomal breakpoint.

Nonsecretory Variant of Immunoproliferative Small Intestinal Disease: A Case Report With Pathologic, Immunophenotypic, and Molecular Findings

2005 ◽  
Vol 129 (11) ◽  
pp. 1487-1490
Author(s):  
Reetesh K. Pai ◽  
Warren K. Snider, MD ◽  
Cindi R. Starkey ◽  
David Viswanatha ◽  
M. Kathryn Foucar ◽  
...  
Keyword(s):  
Heavy Chain ◽  
Light Chain ◽  
Gene Rearrangement ◽  
Intestinal Disease ◽  
Chain Gene ◽  
Light Chain Gene ◽  
Immunoproliferative Small Intestinal Disease ◽  
Igh Gene Rearrangement ◽  
Small Intestinal ◽  
Small Intestinal Disease

Abstract We report a case of the nonsecretory variant of immunoproliferative small intestinal disease involving the distal small bowel and the mesenteric and retroperitoneal lymph nodes in a 19-year-old woman from Mexico. This variant extranodal marginal zone B-cell lymphoma appeared similar in the different sites of involvement, with more interspersed large cells and greater plasmacytic differentiation present in intestinal specimens. Characteristic lymphoepithelial lesions and follicular colonization were seen in intestinal and lymph node sections, respectively. The neoplastic B cells were cytoplasmic immunoglobulin (Ig) A heavy-chain restricted and lacked surface and cytoplasmic light-chain expression by flow cytometric analysis. Serum and urine protein electrophoresis/immunofixation revealed hypogammaglobulinemia with no paraprotein. Molecular studies showed absence of immunoglobulin heavy-chain (IgH) gene rearrangement, with a nonfunctional clonotypic rearrangement of the κ light-chain gene. This case highlights the role for κ light-chain gene evaluation in immunoproliferative small intestinal disease, because IgH gene rearrangement analysis is often negative.

Novel functions of clathrin light chains: clathrin heavy chain trimerization is defective in light chain-deficient yeast

1997 ◽  
Vol 110 (7) ◽  
pp. 899-910 ◽  
Author(s):  
K.M. Huang ◽  
L. Gullberg ◽  
K.K. Nelson ◽  
C.J. Stefan ◽  
K. Blumer ◽  
...  
Keyword(s):  
Heavy Chain ◽  
Light Chain ◽  
State Level ◽  
Light Chains ◽  
Chain Gene ◽  
Light Chain Gene ◽  
Heavy Chains ◽  
Clathrin Heavy Chain ◽  
Multicopy Suppressors ◽  
Delta Cells

Clathrin is a major coat protein involved in sorting and retention of proteins at the late Golgi and in endocytosis from the cell surface. The clathrin triskelion contains three heavy chains, which provide the structural backbone of the clathrin lattice and three light chains, which are thought to regulate the formation or disassembly of clathrin coats. To better understand the function of the clathrin light chain, we characterized yeast strains carrying a disruption of the clathrin light chain gene (CLC1). Light chain-deficient cells showed phenotypes similar to those displayed by yeast that have a disruption in the clathrin heavy chain gene (CHC1). In clc1-delta cells, the steady state level of the clathrin heavy chain was reduced to 20%-25% of wild-type levels and most of the heavy chain was not trimerized. If CHC1 was overexpressed in clc1-delta cells, heavy chain trimers were detected and several clc1-delta phenotypes were partially rescued. These results indicate that the light chain is important for heavy chain trimerization and the heavy chain still has some function in the absence of the light chain. In yeast, deletion of CHC1 is lethal in strains carrying the scd1-i allele, while strains carrying the scd1-v allele can survive without the heavy chain. In previous studies we isolated several multicopy suppressors of inviability of chc1-delta scd1-i cells. Surprisingly, one of these suppressors, SCD4, is identical to CLC1. Overexpression of CLC1 in viable chc1-delta scd1-v strains rescued some but not all of the phenotypes displayed by these cells. In the absence of the heavy chain, the light chain was not found in a high molecular mass complex, but still associated with membranes. These results suggest that the light chain can function independently of the clathrin heavy chain in yeast.

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