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Analysis of a series of gene-targeted mice carrying anti-DNA IgH chains of increasing affinities revealed increasingly restricted L-chain V gene use and editing involving multiple rearrangements. Among the edited cells were those that carried multiple receptors with partial autoreactivity
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This is an interesting mathematical modeling study of receptor editing. One prediction of the model is that allelic inclusion should be a significant mechanism of tolerance
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Single cell analysis of κ gene methylation suggested that only about 60% of κ loci are demethylated in B cells and that these alleles are preferential substrates for recombinase. Monoallelic demethylation should promote allelic exclusion and restrict editing to a single allele
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•] show, in a primary cell culture system using IgH plus L transgenic bone marrow, that deficiency in CD19, but not in CD45, impairs feedback suppression of endogenous L-chain gene rearrangements. Interestingly, the defect in the CD19-deficient mice could be restored by making the transgene homozygous, suggesting that CD19 affects the threshold for basal BCR signaling in this system
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•] show, in a primary cell culture system using IgH plus L transgenic bone marrow, that deficiency in CD19, but not in CD45, impairs feedback suppression of endogenous L-chain gene rearrangements. Interestingly, the defect in the CD19-deficient mice could be restored by making the transgene homozygous, suggesting that CD19 affects the threshold for basal BCR signaling in this system.
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Cutting edge: Absence of expression of RAG1 in peritoneal B-1 cells detected by knocking into RAG1 locus with green fluorescent protein gene
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Kuwata N., Igarashi H., Ohmura T., Aizawa S., Sakaguchi N. Cutting edge: absence of expression of RAG1 in peritoneal B-1 cells detected by knocking into RAG1 locus with green fluorescent protein gene. J. Immunol. 163:2001;6355-6359.
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0035353180
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Localization of recombination activating gene 1/green fluorescent protein (RAG1/GFP) expression in secondary lymphoid organs after immunization with T-dependent antigens in rag1/gfp knockin mice
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This careful study defined the cellular pattern and inducibility of RAG-1 gene expression in peripheral lymphoid organs in mice using a green fluorescent protein (GFP) gene targeted reporter. Although positive cells are observed in spleen and lymph nodes they appear to lie outside of germinal centers and GFP expression was not detectably induced by immunization or in vitro stimulation
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Circulating human B cells that express surrogate light chains and edited receptors
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Meffre E., Davis E., Schiff C., Cunningham-Rundles C., Ivashkiv L.B., Staudt L.M., Young J.W., Nussenzweig M.C. Circulating human B cells that express surrogate light chains and edited receptors. Nat. Immunol. 1:2000;207-213.
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45
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0034686433
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Nagaoka H., Gonzalez-Aseguinolaza G., Tsuji M., Nussenzweig M.C. Immunization and infection change the number of recombination activating gene (RAG)-expressing B cells in the periphery by altering immature lymphocyte production. J. Exp. Med. 191:2000;2113-2120.
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46
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0037079710
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Expression of the recombination-activating genes in extrafollicular lymphocytes but no apparent reinduction in germinal center reactions in human tonsils
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47
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Brard F., Shannon M., Prak E.L., Litwin S., Weigert M. Somatic mutation and light chain rearrangement generate autoimmunity in anti-single-stranded DNA transgenic MRL/lpr mice. J. Exp. Med. 190:1999;691-704.
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de Wildt R., Hoet R.M.A., van Venrooij W.J., Tomlinson I.M., Winter G. Analysis of heavy and light chain pairings indicates that receptor editing shapes the human antibody repertoire. J. Mol. Biol. 285:1999;895-901.
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49
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Hansen A., Dorner T., Lipsky P.E. Use of immunoglobulin variable-region genes by normal subjects and patients with systemic lupus erythematosus. Int. Arch. Allergy Immunol. 123:2000;36-45.
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51
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Itoh K., Meffre E., Albesiano E., Farber A., Dines D., Stein P., Asnis S.E., Furie R.A., Jain R.I., Chiorazzi N. Immunoglobulin heavy chain variable region gene replacement as a mechanism for receptor revision in rheumatoid arthritis synovial tissue B lymphocytes. J. Exp. Med. 192:2000;1151-1164.
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52
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0037144519
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Evolution of autoantibody responses via somatic hypermutation outside of germinal centers
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Autoreactive B cells in IgH transgenic MRL/lpr mice were analyzed by splenic sectioning, microdissection, PCR amplification and L-chain gene sequencing to determine if extrafollicular diversification occurred. The authors found evidence for V gene mutation in cells accumulating at the T cell/ red pulp border, suggesting that hypermutation can occur outside of germinal centers
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William J., Euler C., Christensen S., Shlomchik M.J. Evolution of autoantibody responses via somatic hypermutation outside of germinal centers. Science. 297:2002;2066-2070 Autoreactive B cells in IgH transgenic MRL/lpr mice were analyzed by splenic sectioning, microdissection, PCR amplification and L-chain gene sequencing to determine if extrafollicular diversification occurred. The authors found evidence for V gene mutation in cells accumulating at the T cell/ red pulp border, suggesting that hypermutation can occur outside of germinal centers.
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William, J.1
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53
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Han S., Dillon S.R., Zheng B., Shimoda M., Schlissel M.S., Kelsoe G. V(D)J recombinase activity in a subset of germinal center B lymphocytes. Science. 278:1997;301-305.
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Hertz M., Kouskoff V., Nakamura T., Nemazee D. V(D)J recombinase induction in splenic B lymphocytes is inhibited by antigen-receptor signalling. Nature. 394:1998;292-295.
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55
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Antigen receptor engagement turns off the V(D)J recombination machinery in human tonsil B cells
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Meffre E., Papavasiliou F., Cohen P., de Bouteiller O., Bell D., Karasuyama H., Schiff C., Banchereau J., Liu Y.J., Nussenzweig M.C. Antigen receptor engagement turns off the V(D)J recombination machinery in human tonsil B cells. J. Exp. Med. 188:1998;765-772.
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Meffre, E.1
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56
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0036232602
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Contribution of light chain rearrangement in peripheral B cells to the generation of high-affinity antibodies
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Taking advantage of their observation that RAG expression in peripheral B cells is IL-7 dependent, these investigators tested the effect of anti-IL-7 receptor treatment on affinity maturation and κ/λ usage among antibodies stimulated by immunization of a IgH-chain knock-in mouse with a hapten-protein conjugate. The findings indicate that blocking receptor revision in vivo has a major impact on affinity maturation and suppresses the extent of Igλ antibody production
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Magari M., Sawatari T., Kawano Y., Cascalho M., Wabl M., Kanayama N., Hikida M., Ohmori H. Contribution of light chain rearrangement in peripheral B cells to the generation of high-affinity antibodies. Eur. J. Immunol. 32:2002;957-966 Taking advantage of their observation that RAG expression in peripheral B cells is IL-7 dependent, these investigators tested the effect of anti-IL-7 receptor treatment on affinity maturation and κ/λ usage among antibodies stimulated by immunization of a IgH-chain knock-in mouse with a hapten-protein conjugate. The findings indicate that blocking receptor revision in vivo has a major impact on affinity maturation and suppresses the extent of Igλ antibody production.
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Magari, M.1
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Ohmori, H.8
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57
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0035663555
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Receptor revision plays no major role in shaping the receptor repertoire of human memory B cells after the onset of somatic hypermutation
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H regions tested the notion that the VJκ joins that they often contain were edited after the onset of somatic mutation. Of 265 cells tested, none showed evidence that could unequivocally support the hypothesis, suggesting either that revision made a negligible contribution to diversity or did so only before the onset of somatic mutation
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H regions tested the notion that the VJκ joins that they often contain were edited after the onset of somatic mutation. Of 265 cells tested, none showed evidence that could unequivocally support the hypothesis, suggesting either that revision made a negligible contribution to diversity or did so only before the onset of somatic mutation.
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Goossens, T.1
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58
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Biased Igλ expression in hypermutated IgD multiple myelomas does not result from receptor revision
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van der Burg M., Bende R.J., Aarts W.M., Langerak A.W., van Dongen J.J., van Noesel C.J. Biased Igλ expression in hypermutated IgD multiple myelomas does not result from receptor revision. Leukemia. 16:2002;1358-1361.
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Van der Burg, M.1
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59
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Diaw L., Siwarski D., DuBois W., Jones G., Huppi K. Double producers of kappa and lambda define a subset of B cells in mouse plasmacytomas. Mol. Immunol. 37:2000;775-781.
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60
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0034842962
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Thyroid autoimmune disease: Demonstration of thyroid antigen-specific B cells and recombination-activating gene expression in chemokine-containing active intrathyroidal germinal centers
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Armengol M.P., Juan M., Lucas-Martin A., Fernandez-Figueras M.T., Jaraquemada D., Gallart T., Pujol-Borrell R. Thyroid autoimmune disease: demonstration of thyroid antigen-specific B cells and recombination-activating gene expression in chemokine-containing active intrathyroidal germinal centers. Am. J. Pathol. 159:2001;861-873.
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Armengol, M.P.1
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61
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0034767872
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Expression of recombination-activating genes and terminal deoxynucleotidyl transferase and secondary rearrangement of immunoglobulin κ light chains in rheumatoid arthritis synovial tissue
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Expression of RAG, terminal deoxynucleotidyl transferase (TdT) and recombinase activity were measured in synovial tissue from rheumatoid arthritis patients. The results indicate that receptor revision may occur in this disease
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Zhang Z., Wu X., Limbaugh B.H., Bridges S.L. Jr. Expression of recombination-activating genes and terminal deoxynucleotidyl transferase and secondary rearrangement of immunoglobulin κ light chains in rheumatoid arthritis synovial tissue. Arthritis Rheum. 44:2001;2275-2284 Expression of RAG, terminal deoxynucleotidyl transferase (TdT) and recombinase activity were measured in synovial tissue from rheumatoid arthritis patients. The results indicate that receptor revision may occur in this disease.
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Arthritis Rheum.
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Zhang, Z.1
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Bridges S.L., Jr.4
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62
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0034746711
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Immunoglobulin Vλ light chain gene usage in patients with Sjogren's syndrome
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Extensive single cell sequencing analysis of antibody genes from peripheral blood B cells of three patients found changes in the λ repertoire that suggested defects in selection, editing, and mutational targeting
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Kaschner S., Hansen A., Jacobi A., Reiter K., Monson N.L., Odendahl M., Burmester G.R., Lipsky P.E., Dorner T. Immunoglobulin Vλ light chain gene usage in patients with Sjogren's syndrome. Arthritis Rheum. 44:2001;2620-2632 Extensive single cell sequencing analysis of antibody genes from peripheral blood B cells of three patients found changes in the λ repertoire that suggested defects in selection, editing, and mutational targeting.
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Arthritis Rheum.
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Kaschner, S.1
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63
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Immunoglobulin gene rearrangement analysis in composite Hodgkin disease and large B-cell lymphoma: Evidence for receptor revision of immunoglobulin heavy chain variable region genes in Hodgkin-Reed-Sternberg cells?
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Bellan C., Lazzi S., Zazzi M., Lalinga A.V., Palummo N., Galieni P., Marafioti T., Tonini T., Cinti C., Leoncini L.et al. Immunoglobulin gene rearrangement analysis in composite Hodgkin disease and large B-cell lymphoma: evidence for receptor revision of immunoglobulin heavy chain variable region genes in Hodgkin-Reed-Sternberg cells? Diagn. Mol. Pathol. 11:2002;2-8.
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64
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T-cell receptor α locus V(D)J recombination by-products are abundant in thymocytes and mature T cells
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Livak F., Schatz D.G. T-cell receptor α locus V(D)J recombination by-products are abundant in thymocytes and mature T cells. Mol. Cell Biol. 16:1996;609-618.
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66
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The tight interallelic positional coincidence that distinguishes T-cell receptor Jα usage does not result from homologous chromosomal pairing during VαJα rearrangement
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This study analyzed the recombination status of both TCRα chromosomes in a large number of T cell clones. In almost all clones, rearrangement to a similarly positioned J region occurred on both chromosomes. Fluorescence in situ hybridization (FISH) analysis showed that this positional coincidence could not be explained by the physical juxtaposition of homologous Jα regions. Although a trend was seen for V regions, the positional coincidence was not as tight as for J regions. In-frame rearrangements were found on both alleles in approximately 1/3 clones
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Davodeau F., Difilippantonio M., Roldan E., Malissen M., Casanova J.L., Couedel C., Morcet J.F., Merkenschlager M., Nussenzweig A., Bonneville M., Malissen B. The tight interallelic positional coincidence that distinguishes T-cell receptor Jα usage does not result from homologous chromosomal pairing during VαJα rearrangement. EMBO J. 20:2001;4717-4729 This study analyzed the recombination status of both TCRα chromosomes in a large number of T cell clones. In almost all clones, rearrangement to a similarly positioned J region occurred on both chromosomes. Fluorescence in situ hybridization (FISH) analysis showed that this positional coincidence could not be explained by the physical juxtaposition of homologous Jα regions. Although a trend was seen for V regions, the positional coincidence was not as tight as for J regions. In-frame rearrangements were found on both alleles in approximately 1/3 clones.
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Davodeau, F.1
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Bonneville, M.10
Malissen, B.11
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67
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0037020847
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Quantitative and qualitative changes in V-J alpha rearrangements during mouse thymocytes differentiation: Implication for a limited T cell receptor alpha chain repertoire
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This paper provides a comprehensive analysis of V-J joining frequency in mouse thymocytes. The data support a bi-directional and coordinated model of recombination beginning with the most 3′ V regions and 5′ J regions. The paper also showed that the TCR V and J regions become gradually accessible from day 18 in gestation until one day after birth
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Pasqual N., Gallagher M., Aude-Garcia C., Loiodice M., Thuderoz F., Demongeot J., Ceredig R., Marche P.N., Jouvin-Marche E. Quantitative and qualitative changes in V-J alpha rearrangements during mouse thymocytes differentiation: implication for a limited T cell receptor alpha chain repertoire. J. Exp. Med. 196:2002;1163-1174 This paper provides a comprehensive analysis of V-J joining frequency in mouse thymocytes. The data support a bi-directional and coordinated model of recombination beginning with the most 3′ V regions and 5′ J regions. The paper also showed that the TCR V and J regions become gradually accessible from day 18 in gestation until one day after birth.
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Pasqual, N.1
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68
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This study used a large YAC transgene to drive expression of RAG genes in RAG deficient mice. RAG levels were high in DN cells and much lower in DP cells, consistent with the lack of a cis-acting regulatory element for re-induction of RAG after β selection. In such mice, TCRα locus rearrangement was restricted to the most 5′ J elements, with no secondary recombination. This resulted in a significant reduction in mature T cell numbers, suggesting that a majority of mature T cells are products of secondary recombination
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Yannoutsos N., Wilson P., Yu W., Chen H.T., Nussenzweig A., Petrie H., Nussenzweig M.C. The role of recombination activating gene (RAG) reinduction in thymocyte development in vivo. J. Exp. Med. 194:2001;471-480 This study used a large YAC transgene to drive expression of RAG genes in RAG deficient mice. RAG levels were high in DN cells and much lower in DP cells, consistent with the lack of a cis-acting regulatory element for re-induction of RAG after β selection. In such mice, TCRα locus rearrangement was restricted to the most 5′ J elements, with no secondary recombination. This resulted in a significant reduction in mature T cell numbers, suggesting that a majority of mature T cells are products of secondary recombination.
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Yannoutsos, N.1
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69
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70
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Heath W.R., Carbone F.R., Bertolino P., Kelly J., Cose S., Miller J.F. Expression of two T cell receptor α chains on the surface of normal murine T cells. Eur. J. Immunol. 25:1995;1617-1623.
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71
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Alam S.M., Gascoigne N.R. Posttranslational regulation of TCR Vα allelic exclusion during T cell differentiation. J. Immunol. 160:1998;3883-3890.
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72
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Maintenance of TCR clonality in T cells expressing genes for two TCR heterodimers
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This paper reports the surprising finding that in certain double TCR transgenic mouse strains, T cells expressed only one receptor or the other. As T cells expressed mRNA and protein from both receptors, the authors propose a post-translational allelic exclusion mechanism related to the TCR assembly process
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Sant'Angelo D.B., Cresswell P., Janeway C.A. Jr., Denzin L.K. Maintenance of TCR clonality in T cells expressing genes for two TCR heterodimers. Proc. Natl. Acad. Sci. USA. 98:2001;6824-6829 This paper reports the surprising finding that in certain double TCR transgenic mouse strains, T cells expressed only one receptor or the other. As T cells expressed mRNA and protein from both receptors, the authors propose a post-translational allelic exclusion mechanism related to the TCR assembly process.
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Sant'Angelo, D.B.1
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74
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Brandle D., Muller S., Muller C., Hengartner H., Pircher H. Regulation of RAG-1 and CD69 expression in the thymus during positive and negative selection. Eur. J. Immunol. 24:1994;145-151.
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76
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Wang F., Huang C.Y., Kanagawa O. Rapid deletion of rearranged T cell antigen receptor (TCR) Vα-Jα segment by secondary rearrangement in the thymus: role of continuous rearrangement of TCRα chain gene and positive selection in the T cell repertoire formation. Proc. Natl. Acad. Sci. USA. 95:1998;11834-11839.
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78
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