Key Points
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Receptor editing occurs when a signal transmitted by an autoreactive B-cell receptor (BCR) stimulates or sustains secondary V(D)J recombinations in the gene encoding the antigen receptor, leading to alteration of the specificity of the cell. This is the dominant mechanism of tolerance induction for immature B cells. Receptor editing has also been documented for some cases of central T-cell tolerance (in the thymus). And receptor-editing-like events occur in other contexts, such as in the thymus, where intact antigen receptors can be edited as a result of there being insufficient signal strength for the cell to be positively selected, a process that is normally required to terminate recombination at the locus that encodes the α-chain of the T-cell receptor (TCRα).
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There are many similarities between the different types of lymphocyte in the adaptive immune system (that is, B cells, αβT cells and γδ T cells) in terms of the organization and the regulation of their antigen-receptor genes. In particular, each cell type has an asymmetry in the genetic features of its two antigen-receptor chains, favouring generation of diversity in one and receptor editing in the other.
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The heterodimeric antigen receptor of each lymphocyte type carries one receptor chain with a variable region that consists of V (variable), D (diversity) and J (joining) minigene elements, whereas the variable region of the other receptor chain is encoded by only V and J elements.
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The asymmetry in D-element usage causes large differences in the contributions of the two chains to overall diversity, with most diversity provided by chains that contain D-element-encoded amino-acid residues.
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During lymphocyte development, receptor chains with a D-element-encoded region are recombined and expressed at an earlier stage in development than are receptor chains that lack such a region. In precursor (pre)-T cells and precursor (pre)-B cells, the first receptor chains to be rearranged are tested by assembly with surrogate second receptor chains to generate pre-BCRs and pre-TCRs. Pre-BCR and pre-TCR signalling are important in promoting cell maturation and in preventing functional expression of both alleles.
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The gene structure of the second receptor chain and the nonrandom hierarchy of rearrangement seem to facilitate secondary rearrangements and receptor editing.
Abstract
The specificities of lymphocytes for antigen are generated by a quasi-random process of gene rearrangement that often results in non-functional or autoreactive antigen receptors. Regulation of lymphocyte specificities involves not only the elimination of cells that display 'unsuitable' receptors for antigen but also the active genetic correction of these receptors by secondary recombination of the DNA. As I discuss here, an important mechanism for the genetic correction of antigen receptors is ongoing recombination, which leads to receptor editing. Receptor editing is probably an adaptation that is necessitated by the high probability of receptor autoreactivity. In both B cells and T cells, the genes that encode the two chains of the antigen receptor seem to be specialized to promote, on the one hand, the generation of diverse specificities and, on the other hand, the regulation of these specificities through efficient editing.
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References
Burnet, F. M. The Clonal Selection Theory of Acquired Immunity (Cambridge Univ. Press, Cambridge, 1959).
Nemazee, D. Receptor selection in B and T lymphocytes. Annu. Rev. Immunol. 18, 19–51 (2000).
Nemazee, D. & Weigert, M. Revising B cell receptors. J. Exp. Med. 191, 1813–1817 (2000).
Mostoslavsky, R. & Alt, F. W. Receptor revision in T cells: an open question? Trends Immunol. 25, 276–279 (2004).
Tonegawa, S. Somatic generation of antibody diversity. Nature 302, 575–581 (1983).
Janeway, C. A., Travers, P., Walport, M. & Shlomchik, M. Immunobiology 5th edn (Garland, New York, 2001).
Schlissel, M. S. Regulating antigen-receptor gene assembly. Nature Rev. Immunol. 3, 890–899 (2003).
Louzoun, Y., Friedman, T., Luning Prak, E., Litwin, S. & Weigert, M. Analysis of B cell receptor production and rearrangement. Part I. Light chain rearrangement. Semin. Immunol. 14, 169–190; discussion 221–222 (2002).
Davis, M. M. & Bjorkman, P. J. T-cell antigen receptor genes and T-cell recognition. Nature 334, 395–402 (1988); erratum in 335, 744 (1988).
Gilfillan, S., Benoist, C. & Mathis, D. Mice lacking terminal deoxynucleotidyl transferase: adult mice with a fetal antigen receptor repertoire. Immunol. Rev. 148, 201–219 (1995).
Ippolito, G. C. et al. Forced usage of positively charged amino acids in immunoglobulin CDR-H3 impairs B cell development and antibody production. J. Exp. Med. 203, 1567–1578 (2006).
Pricop, L. et al. Antibody response elicited by T-dependent and T-independent antigens in gene targeted κ-deficient mice. Int. Immunol. 6, 1839–1847 (1994).
Xu, J. L. & Davis, M. M. Diversity in the CDR3 region of VH is sufficient for most antibody specificities. Immunity 13, 37–45 (2000).
Alt, F. W. et al. Ordered rearrangement of immunoglobulin heavy chain variable region segments. EMBO J. 3, 1209–1219 (1984).
Li, Y. S., Hayakawa, K. & Hardy, R. R. The regulated expression of B lineage associated genes during B cell differentiation in bone marrow and fetal liver. J. Exp. Med. 178, 951–960 (1993).
Coleclough, C. Chance, necessity and antibody gene dynamics. Nature 303, 23–26 (1983).
Nussenzweig, M. C. et al. Allelic exclusion in transgenic mice that express the membrane form of immunoglobulin μ. Science 236, 816–819 (1987).
Manz, J. et al. Feedback inhibition of immunoglobulin gene rearrangement by membrane μ, but not by secreted μ heavy chains. J. Exp. Med. 168, 1363–1381 (1988); erratum in 169, 2269 (1989).
Kitamura, D. & Rajewsky, K. Targeted disruption of μ chain membrane exon causes loss of heavy-chain allelic exclusion. Nature 356, 154–156 (1992).
Ehlich, A., Martin, V., Muller, W. & Rajewsky, K. Analysis of the B-cell progenitor compartment at the level of single cells. Curr. Biol. 4, 573–583 (1994).
Melchers, F. The pre-B-cell receptor: selector of fitting immunoglobulin heavy chains for the B-cell repertoire. Nature Rev. Immunol. 5, 578–584 (2005).
Karasuyama, H. et al. The expression of Vpre-B/λ5 surrogate light chain in early bone marrow precursor B cells of normal and B cell-deficient mutant mice. Cell 77, 133–143 (1994).
ten Boekel, E., Melchers, F. & Rolink, A. G. Precursor B cells showing H chain allelic inclusion display allelic exclusion at the level of pre-B cell receptor surface expression. Immunity 8, 199–207 (1998).
Decker, D. J., Boyle, N. E. & Klinman, N. R. Predominance of nonproductive rearrangements of VH81X gene segments evidences a dependence of B cell clonal maturation on the structure of nascent H chains. J. Immunol. 147, 1406–1411 (1991).
Hardy, R. R. et al. Resolution and characterization of pro-B and pre-pro-B cell stages in normal mouse bone marrow. J. Exp. Med. 173, 1213–1225 (1991).
Shimizu, T. et al. VpreB1/VpreB2/λ5 triple-deficient mice show impaired B cell development but functional allelic exclusion of the IgH locus. J. Immunol. 168, 6286–6293 (2002).
Wasserman, R. et al. A novel mechanism for B cell repertoire maturation based on response by B cell precursors to pre-B receptor assembly. J. Exp. Med. 187, 259–264 (1998).
von Boehmer, H. & Fehling, H. J. Structure and function of the pre-T cell receptor. Annu. Rev. Immunol. 15, 433–452 (1997).
Groettrup, M. et al. A novel disulfide-linked heterodimer on pre-T cells consists of the T cell receptor β chain and a 33 kd glycoprotein. Cell 75, 283–294 (1993).
von Boehmer, H. Unique features of the pre-T-cell receptor α-chain: not just a surrogate. Nature Rev. Immunol. 5, 571–577 (2005).
Jameson, S. C., Hogquist, K. A. & Bevan, M. J. Positive selection of thymocytes. Annu. Rev. Immunol. 13, 93–126 (1995).
Livak, F., Tourigny, M., Schatz, D. G. & Petrie, H. T. Characterization of TCR gene rearrangements during adult murine T cell development. J. Immunol. 162, 2575–2580 (1999).
Joachims, M. L. et al. Human αβ and γδ thymocyte development: TCR gene rearrangements, intracellular TCRβ expression, and γδ developmental potential —differences between men and mice. J. Immunol. 176, 1543–1552 (2006).
Hayes, S. M., Li, L. & Love, P. E. TCR signal strength influences αβ/γδ lineage fate. Immunity 22, 583–593 (2005).
Krueger, A., Garbe, A. I. & von Boehmer, H. Phenotypic plasticity of T cell progenitors upon exposure to Notch ligands. J. Exp. Med. 203, 1977–1984 (2006).
Chien, Y.-H. et al. T-cell receptor δ gene rearrangements in early thymocytes. Nature 330, 722–727 (1987).
Carroll, A. M. & Bosma, M. J. T-lymphocyte development in scid mice is arrested shortly after the initiation of T-cell receptor δ gene recombination. Genes Dev. 5, 1357–1366 (1991).
Boucontet, L., Sepulveda, N., Carneiro, J. & Pereira, P. Mechanisms controlling termination of V-J recombination at the TCRγ locus: implications for allelic and isotypic exclusion of TCRγ chains. J. Immunol. 174, 3912–3919 (2005).
Barreto, V. & Cumano, A. Frequency and characterization of phenotypic Ig heavy chain allelically included IgM-expressing B cells in mice. J. Immunol. 164, 893–899 (2000). This study provides the best estimate of allelic exclusion of Igh in mice, on the basis of cell-surface expression.
Khor, B. & Sleckman, B. P. Intra- and inter-allelic ordering of T cell receptor β chain gene assembly. Eur. J. Immunol. 35, 964–970 (2005).
Sleckman, B. P., Khor, B., Monroe, R. & Alt, F. W. Assembly of productive T cell receptor δ variable region genes exhibits allelic inclusion. J. Exp. Med. 188, 1465–1471 (1998). This study of mouse hybridomas provides strong evidence that allelic inclusion of Tcrd occurs frequently.
Ferrero, I. et al. T cell receptor specificity is critical for the development of epidermal γδ T cells. J. Exp. Med. 194, 1473–1483 (2001).
Chowdhury, D. & Sen, R. Mechanisms for feedback inhibition of the immunoglobulin heavy chain locus. Curr. Opin. Immunol. 16, 235–240 (2004).
Tripathi, R., Jackson, A. & Krangel, M. S. A change in the structure of Vβ chromatin associated with TCRβ allelic exclusion. J. Immunol. 168, 2316–2324 (2002).
Kosak, S. T. et al. Subnuclear compartmentalization of immunoglobulin loci during lymphocyte development. Science 296, 158–162 (2002).
Roldan, E. et al. Locus 'decontraction' and centromeric recruitment contribute to allelic exclusion of the immunoglobulin heavy-chain gene. Nature Immunol. 6, 31–41 (2005).
Bolland, D. J. et al. Antisense intergenic transcription in V(D)J recombination. Nature Immunol. 5, 630–637 (2004).
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, 609–618 (1996).
Petrie, H. T. et al. Multiple rearrangements in T cell receptor α chain genes maximize the production of useful thymocytes. J. Exp. Med. 178, 615–622 (1993).
Hawwari, A. & Krangel, M. S. Regulation of TCR δ and α repertoires by local and long-distance control of variable gene segment chromatin structure. J. Exp. Med. 202, 467–472 (2005).
Hawwari, A., Bock, C. & Krangel, M. S. Regulation of T cell receptor α gene assembly by a complex hierarchy of germline Jα promoters. Nature Immunol. 6, 481–489 (2005).
Wood, D. L. & Coleclough, C. Different joining region J elements of the murine κ immunoglobulin light chain locus are used at markedly different frequencies. Proc. Natl Acad. Sci. USA 81, 4756–4760 (1984).
Constantinescu, A. & Schlissel, M. S. Changes in locus-specific V(D)J recombinase activity induced by immunoglobulin gene products during B cell development. J. Exp. Med. 185, 609–620 (1997).
Mostoslavsky, R. et al. κ Chain monoallelic demethylation and the establishment of allelic exclusion. Genes Dev. 12, 1801–1811 (1998).
Bemark, M., Liberg, D. & Leanderson, T. Conserved sequence elements in κ promoters from mice and humans: implications for transcriptional regulation and repertoire expression. Immunogenetics 47, 183–195 (1998).
Casellas, R. et al. OcaB is required for normal transcription and V(D)J recombination of a subset of immunoglobulin κ genes. Cell 110, 575–585 (2002).
Arakawa, H., Shimizu, T. & Takeda, S. Re-evaluation of the probabilities for productive arrangements on the κ and λ loci. Int. Immunol. 8, 91–99 (1996).
Klein, F. et al. Tracing the pre-B to immature B cell transition in human leukemia cells reveals a coordinated sequence of primary and secondary IGK gene rearrangement, IGK deletion, and IGL gene rearrangement. J. Immunol. 174, 367–375 (2005).
Gay, D., Saunders, T., Camper, S. & Weigert, M. Receptor editing: an approach by autoreactive B cells to escape tolerance. J. Exp. Med. 177, 999–1008 (1993). Together with reference 61, this paper provides the first evidence of receptor editing in vivo.
Radic, M. Z., Erikson, J., Litwin, S. & Weigert, M. B lymphocytes may escape tolerance by revising their antigen receptors. J. Exp. Med. 177, 1165–1173 (1993).
Tiegs, S. L., Russell, D. M. & Nemazee, D. Receptor editing in self-reactive bone marrow B cells. J. Exp. Med. 177, 1009–1020 (1993).
Hertz, M. & Nemazee, D. BCR ligation induces receptor editing in IgM+IgD− bone marrow B cells in vitro. Immunity 6, 429–436 (1997).
Lam, K. P. & Rajewsky, K. Rapid elimination of mature autoreactive B cells demonstrated by Cre-induced change in B cell antigen receptor specificity in vivo. Proc. Natl Acad. Sci. USA 95, 13171–13175 (1998).
Hartley, S. B. et al. Elimination of self-reactive B lymphocytes proceeds in two stages: arrested development and cell death. Cell 72, 325–335 (1993).
Melamed, D. & Nemazee, D. Self-antigen does not accelerate immature B cell apoptosis, but stimulates receptor editing as a consequence of developmental arrest. Proc. Natl Acad. Sci. USA 94, 9267–9272 (1997). This paper describes the development of a useful cell-culture model to study receptor editing in B cells.
Casellas, R. et al. Contribution of receptor editing to the antibody repertoire. Science 291, 1541–1544 (2001). This study provides compelling evidence of the high frequency of receptor editing in a polyclonal B-cell population.
Luning Prak, E., Trounstine, M., Huszar, D. & Weigert, M. Light chain editing in κ-deficient animals: a potential mechanism of B cell tolerance. J. Exp. Med. 180, 1805–1815 (1994).
Luning Prak, E. & Weigert, M. Light chain replacement: a new model for antibody gene rearrangement. J. Exp. Med. 182, 541–548 (1995). The first mice with a site-directed transgene encoding the IgL chain were developed, and it was shown that a high frequency of receptor editing occurs in polyclonal B-cell populations.
Durdik, J., Moore, M. W. & Selsing, E. Novel κ light-chain gene rearrangements in mouse λ light chain-producing B lymphocytes. Nature 307, 749–752 (1984).
Siminovitch, K. A., Moore, M. W., Durdik, J. & Selsing, E. The human κ deleting element and the mouse recombining segment share DNA sequence homology. Nucleic Acids Res. 15, 2699–2705 (1987).
Selsing, E. & Daitch, L. E. in Immunoglobulin Genes 2nd edn (eds Honjo, T. & Alt, F.) 194–203 (Academic, London, 1995).
Chen, C., Luning Prak, E. & Weigert, M. Editing disease-associated autoantibodies. Immunity 6, 97–105 (1997). This study provided the first evidence of the efficiency of receptor editing and showed that IgL-chain editing, rather than V H -element replacement, is dominant in immature B cells.
Kouskoff, V. et al. B cell receptor expression level determines the fate of developing B lymphocytes: receptor editing versus selection. Proc. Natl Acad. Sci. USA 97, 7435–7439 (2000).
Braun, U., Rajewsky, K. & Pelanda, R. Different sensitivity to receptor editing of B cells from mice hemizygous or homozygous for targeted Ig transgenes. Proc. Natl Acad. Sci. USA 97, 7429–7434 (2000).
Yachimovich, N. et al. The efficiency of B cell receptor (BCR) editing is dependent on BCR light chain rearrangement status. Eur. J. Immunol. 32, 1164–1174 (2002).
Wellmann, U., Werner, A. & Winkler, T. H. Altered selection processes of B lymphocytes in autoimmune NZB/W mice, despite intact central tolerance against DNA. Eur. J. Immunol. 31, 2800–2810 (2001).
Halverson, R., Torres, R. M. & Pelanda, R. Receptor editing is the main mechanism of B cell tolerance toward membrane antigens. Nature Immunol. 5, 645–650 (2004).
Novobrantseva, T. et al. Stochastic pairing of Ig heavy and light chains frequently generates B cell antigen receptors that are subject to editing in vivo. Int. Immunol. 17, 343–350 (2005). This paper indicates the high probability that random IgH-chain–IgL-chain pairs are autoreactive and induce receptor editing in vivo.
Li, H. et al. Editors and editing of anti-DNA receptors. Immunity 15, 947–957 (2001).
Radic, M. Z. et al. Ig H and L chain contributions to autoimmune specificities. J. Immunol. 146, 176–182 (1991).
Wardemann, H., Hammersen, J. & Nussenzweig, M. C. Human autoantibody silencing by immunoglobulin light chains. J. Exp. Med. 200, 191–199 (2004).
Pewzner-Jung, Y. et al. B cell deletion, anergy, and receptor editing in 'knock in' mice targeted with a germline-encoded or somatically mutated anti-DNA heavy chain. J. Immunol. 161, 4634–4645 (1998).
Li, H. et al. Regulation of anti-phosphatidylserine antibodies. Immunity 18, 185–192 (2003).
Förster, I. & Rajewsky, K. The bulk of the peripheral B-cell pool in mice is stable and not rapidly renewed from the bone marrow. Proc. Natl Acad. Sci. USA 87, 4781–4784 (1990).
Ait-Azzouzene, D. et al. An immunoglobulin Cκ-reactive single chain antibody fusion protein induces tolerance through receptor editing in a normal polyclonal immune system. J. Exp. Med. 201, 817–828 (2005). Using a novel synthetic superantigen that binds Igκ, this study shows, in a polyclonal system, that receptor editing is an efficient mechanism of tolerance induction.
Lang, J. et al. B cells are exquisitely sensitive to central tolerance and receptor editing induced by ultralow affinity, membrane-bound antigen. J. Exp. Med. 184, 1685–1697 (1996).
Erikson, J. et al. Expression of anti-DNA immunoglobulin transgenes in non-autoimmune mice. Nature 349, 331–334 (1991). This paper provided the first evidence that autoreactive B cells carrying disease-associated antibody specificities could be regulated by tolerance.
Goodnow, C. C. et al. Altered immunoglobulin expression and functional silencing of self-reactive B lymphocytes in transgenic mice. Nature 334, 676–682 (1988).
Hippen, K. L. et al. In vivo assessment of the relative contributions of deletion, anergy, and editing to B cell self-tolerance. J. Immunol. 175, 909–916 (2005).
Ait-Azzouzene, D. et al. Split tolerance in peripheral B cell subsets in mice expressing a low level of Igκ-reactive ligand. J. Immunol. 176, 939–948 (2006).
Hayakawa, K. et al. Positive selection of natural autoreactive B cells. Science 285, 113–116 (1999). This study provided the first evidence that B1 cells require positive selection on self antigen.
Chumley, M. J. et al. A VH11Vκ9 B cell antigen receptor drives generation of CD5+ B cells both in vivo and in vitro. J. Immunol. 164, 4586–4593 (2000).
Tatu, C. & Clarke, S. H. Selective maturation of VH12 B cells in the spleen enriches for anti-phosphatidyl choline B cells: evidence for receptor editing. Curr. Top. Microbiol. Immunol. 252, 77–86 (2000).
Hayakawa, K. et al. Positive selection of anti-Thy-1 autoreactive B-1 cells and natural serum autoantibody production independent from bone marrow B cell development. J. Exp. Med. 197, 87–99 (2003).
Ferry, H. et al. The cellular location of self-antigen determines the positive and negative selection of autoreactive B cells. J. Exp. Med. 198, 1415–1425 (2003).
Verkoczy, L. K., Martensson, A. S. & Nemazee, D. The scope of receptor editing and its association with autoimmunity. Curr. Opin. Immunol. 16, 808–814 (2004).
Liu, S. et al. Receptor editing can lead to allelic inclusion and development of B cells that retain antibodies reacting with high avidity autoantigens. J. Immunol. 175, 5067–5076 (2005).
Doyle, C. M., Han, J., Weigert, M. G. & Prak, E. T. Consequences of receptor editing at the λ locus: multireactivity and light chain secretion. Proc. Natl Acad. Sci. USA 103, 11264–11269 (2006).
Witsch, E. J., Cao, H., Fukuyama, H. & Weigert, M. Light chain editing generates polyreactive antibodies in chronic graft-versus-host reaction. J. Exp. Med. 203, 1761–1772 (2006).
Sekiguchi, D. R. et al. Development and selection of edited B cells in B6.56R mice. J. Immunol. 176, 6879–6887 (2006).
Kleinfield, R. et al. Recombination between an expressed immunoglobulin heavy-chain gene and a germline variable gene segment in a Ly1+ B-cell lymphoma. Nature 322, 843–846 (1986).
Reth, M., Gehrmann, P., Petrac, E. & Wiese, P. A novel VH to VHDJH joining mechanism in heavy-chain-negative (null) pre-B cells results in heavy-chain production. Nature 322, 840–842 (1986).
Chen, C., Nagy, Z., Luning Prak, E. & Weigert, M. Immunoglobulin heavy chain gene replacement: a mechanism of receptor editing. Immunity 3, 747–755 (1995).
Taki, S., Schwenk, F. & Rajewsky, K. Rearrangement of upstream DH and VH genes to a rearranged immunoglobulin variable region gene inserted into the DQ52-JH region of the immunoglobulin heavy chain locus. Eur. J. Immunol. 25, 1888–1896 (1995).
Cascalho, M. et al. A quasi-monoclonal mouse. Science 272, 1649–1652 (1996).
Nadel, B., Tang, A. & Feeney, A. J. VH replacement is unlikely to contribute significantly to receptor editing due to an ineffectual embedded recombination signal sequence. Mol. Immunol. 35, 227–232 (1998).
Fanning, L., Bertrand, F. E., Steinberg, C. & Wu, G. E. Molecular mechanisms involved in receptor editing at the Ig heavy chain locus. Int. Immunol. 10, 241–246 (1998).
Watson, L. C. et al. Paucity of V-D-D-J rearrangements and VH replacement events in lupus prone and nonautoimmune TdT−/− and TdT+/+ mice. J. Immunol. 177, 1120–1128 (2006).
Zhang, Z. et al. Contribution of VH gene replacement to the primary B cell repertoire. Immunity 19, 21–31 (2003).
Allman, D. M., Ferguson, S. E. & Cancro, M. P. Peripheral B cell maturation. I. Immature peripheral B cells in adults are heat-stable antigenhi and exhibit unique signaling characteristics. J. Immunol. 149, 2533–2540 (1992).
de Boer, R. J. & Perelson, A. S. How diverse should the immune system be? Proc. Biol. Sci. 252, 171–175 (1993).
Louzoun, Y. et al. Comment on Langman and Cohn. Semin. Immunol. 14, 231–232 (2002).
Nemazee, D. Antigen receptor 'capacity' and the sensitivity of self-tolerance. Immunol. Today 17, 25–29 (1996).
Retter, M. W. & Nemazee, D. Receptor editing occurs frequently during normal B cell development. J. Exp. Med. 188, 1231–1238 (1998). This study provided the first evidence that receptor editing occurs often in normal B cells.
Wardemann, H. et al. Predominant autoantibody production by early human B cell precursors. Science 301, 1374–1377 (2003).
Yamagami, T. et al. Frequencies of multiple IgL chain gene rearrangements in single normal or κL chain-deficient B lineage cells. Immunity 11, 317–327 (1999).
Gerdes, T. & Wabl, M. Autoreactivity and allelic inclusion in a B cell nuclear transfer mouse. Nature Immunol. 5, 1282–1287 (2004).
Kishimoto, H. & Sprent, J. Negative selection in the thymus includes semimature T cells. J. Exp. Med. 185, 263–271 (1997).
Brandle, D. et al. Engagement of the T-cell receptor during positive selection in the thymus down-regulates RAG-1 expression. Proc. Natl Acad. Sci. USA 89, 9529–9533 (1992).
Borgulya, P., Kishi, H., Uematsu, Y. & von Boehmer, H. Exclusion and inclusion of α and β T cell receptor alleles. Cell 69, 529–537 (1992).
Takeshita, S., Toda, M. & Yamagishi, H. Excision products of the T cell receptor gene support a progressive rearrangement model of the α/δ locus. EMBO J. 8, 3261–3270 (1989).
Petrie, H. T., Livak, F., Burtrum, D. & Mazel, S. T cell receptor gene recombination patterns and mechanisms: cell death, rescue, and T cell production. J. Exp. Med. 182, 121–127 (1995).
Davodeau, F. et al. 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, 4717–4729 (2001).
Stockinger, B. T lymphocyte tolerance: from thymic deletion to peripheral control mechanisms. Adv. Immunol. 71, 229–265 (1999).
Kisielow, P. et al. Tolerance in T-cell-receptor transgenic mice involves deletion of nonmature CD4+8+ thymocytes. Nature 333, 742–746 (1988).
Sha, W. C. et al. Positive and negative selection of an antigen receptor on T cells in transgenic mice. Nature 336, 73–76 (1988).
Takahama, Y. & Singer, A. Post-transcriptional regulation of early T cell development by T cell receptor signals. Science 258, 1456–1462 (1992).
Nemazee, D. & Hogquist, K. A. Antigen receptor selection by editing or downregulation of V(D)J recombination. Curr. Opin. Immunol. 15, 182–189 (2003).
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 TCR α chain gene and positive selection in the T cell repertoire formation. Proc. Natl Acad. Sci. USA 95, 11834–11839 (1998).
McGargill, M. A., Derbinski, J. M. & Hogquist, K. A. Receptor editing in developing T cells. Nature Immunol. 1, 336–341 (2000). This paper provided the first clear evidence of receptor editing to achieve tolerance in thymocytes.
Buch, T., Rieux-Laucat, F., Forster, I. & Rajewsky, K. Failure of HY-specific thymocytes to escape negative selection by receptor editing. Immunity 16, 707–718 (2002).
Baldwin, T. A., Sandau, M. M., Jameson, S. C. & Hogquist, K. A. The timing of TCRα expression critically influences T cell development and selection. J. Exp. Med. 202, 111–121 (2005). This paper shows that TCR-transgenic mice express the TCR prematurely, which might lead to misleading conclusions about mechanisms of tolerance.
Bensimon, C., Chastagner, P. & Zouali, M. Human lupus anti-DNA autoantibodies undergo essentially primary Vκ gene rearrangements. EMBO J. 13, 2951–2962 (1994).
Suzuki, N., Harada, T., Mihara, S. & Sakane, T. Characterization of a germline Vκ gene encoding cationic anti-DNA antibody and role of receptor editing for development of the autoantibody in patients with systemic lupus erythematosus. J. Clin. Invest. 98, 1843–1850 (1996).
Dorner, T., Foster, S. J., Farner, N. L. & Lipsky, P. E. Immunoglobulin κ chain receptor editing in systemic lupus erythematosus. J. Clin. Invest. 102, 688–694 (1998).
Li, Y., Li, H., Ni, D. & Weigert, M. Anti-DNA B cells in MRL/lpr mice show altered differentiation and editing pattern. J. Exp. Med. 196, 1543–1552 (2002).
Sekiguchi, D. R., Eisenberg, R. A. & Weigert, M. Secondary heavy chain rearrangement: a mechanism for generating anti-double-stranded DNA B cells. J. Exp. Med. 197, 27–39 (2003).
Yachimovich-Cohen, N. et al. Autoimmune NZB/NZW F1 mice utilize B cell receptor editing for generating high-affinity anti-dsDNA autoantibodies from low-affinity precursors. Eur. J. Immunol. 33, 2469–2478 (2003).
Fugmann, S. D. et al. The RAG proteins and V(D)J recombination: complexes, ends, and transposition. Annu. Rev. Immunol. 18, 495–527 (2000).
Davis, M. M. The evolutionary and structural 'logic' of antigen receptor diversity. Semin. Immunol. 16, 239–243 (2004).
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This work was supported by a grant from the National Institutes of Health (USA).
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Glossary
- γδ T cells
-
T cells that express T-cell receptors consisting of a γ-chain and a δ-chain. These T cells are present mainly in the intestinal epithelium as intraepithelial lymphocytes (IELs). Although the exact function of γδ T cells (or IELs) is still unknown, it has been suggested that mucosal γδ T cells are involved in innate immune responses by the mucosal immune system.
- Central lymphoid tissues
-
The tissues in which lymphocyte development takes place: for B cells, the bone marrow; and for T cells, the thymus.
- Receptor selection
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A feedback mechanism by which the antigen receptor of a lymphocyte can signal either to cease V(D)J recombination or to continue V(D)J recombination, thereby controlling the maintenance or the alteration of antigen-receptor specificity, respectively.
- Central-tolerance mechanism
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A mechanism that occurs at the level of the central lymphoid tissues and creates tolerance to self antigens. Developing B cells, in the bone marrow, and T cells, in the thymus, that strongly recognize self antigen need to undergo further rearrangement of antigen-receptor genes to become tolerant to self, otherwise they face deletion.
- Recombination signal sequence
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(RSS). A conserved element that is recognized by the recombinases involved in V(D)J recombination, which are encoded by recombination-activating gene 1 (RAG1) and RAG2. These sites consist of a palindromic heptamer that is immediately adjacent to the coding minigene elements — the V (variable), D (diversity) and J (joining) elements — and is separated by a 12- or 23-base-pair spacer from a relatively conserved nonamer.
- Combinatorial diversity
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The contribution to antigen-receptor diversity that is provided by the independent recombination of different V (variable), D (diversity) and J (joining) minigene elements and the independent association of the two receptor chains. Combinatorial diversity is usually estimated by taking the product of the number of minigene elements that can be independently associated.
- Junctional diversity
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The contribution to antigen-receptor diversity that is provided by variability at recombination junctions. Owing to the regulated imprecision of V(D)J-recombination mechanisms, the recombination of any two minigene elements can lead to several distinct DNA junctions. One contributor to variability at junctions is the addition of non-template-encoded (N) nucleotides by the enzyme terminal deoxynucleotidyltransferase, which is specific to progenitor (pro)-lymphocytes. Another source of variability is created by the formation and the subsequent resolution of DNA hairpins, leading to the possible addition of micro-palindrome (P) nucleotides.
- Complementarity-determining regions
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(CDRs). The most variable parts of immunoglobulin molecules and T-cell receptors. These regions form loops that make contact with specific ligands. There are three such regions — CDR1, CDR2 and CDR3 — in each V (variable) domain, with CDR3 arising from V(D)J recombination and therefore being the most variable CDR.
- Positive selection
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The survival of developing lymphocytes with 'desirable' antigen receptors is favoured by the processes of positive selection, which include cessation of V(D)J recombination and developmental progression. For double-positive (CD4+CD8+) thymocytes, positive selection is also associated with commitment to the CD4+ or CD8+ T-cell-lineage programme, including functional differentiation and permanent downregulation of the other co-receptor. For thymocytes, weak reactivity to peptide–MHC complexes displayed at the surface of cortical thymic epithelial cells is required for positive selection. For B cells, however, requirement for an antigen-receptor ligand has only been shown for fetal-lineage B1 cells.
- Allelic exclusion
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In theory, every B cell has the potential to produce two immunoglobulin heavy (IgH) chains, as well as two Igκ and two Igλ immunoglobulin light (IgL) chains: one from each chromosome. In practice, however, a B cell produces only one IgH chain and one IgL chain. The process by which the production of two different IgH or IgL chains is prevented is known as allelic exclusion. That individual B cells express only Igκ or Igλ, but not both, is sometimes called isotypic exclusion.
- Deacetylation
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Acetylation is a post-translational modification of chromatin components, particularly histones. It correlates with actively transcribed chromatin. Histone deacetylases have been identified as components of nuclear co-repressor complexes, which reverse the actions of histone acetyltransferases, thereby inhibiting gene transcription.
- Methylation
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During the rearrangement of antigen-receptor genes, only loci from which methyl groups have been removed rearrange efficiently.
- Anergy
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A state of non-responsiveness to antigen. Anergic T cells or B cells cannot respond to their cognate antigens under optimal conditions of stimulation.
- Hybridoma
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A lymphocyte that has been immortalized by fusion with a tumour cell.
- BCR superantigen
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(B-cell-receptor superantigen). A ligand that can bind a large proportion of all BCRs. Examples include protein A of staphylococci (which binds the variable region of immunoglobulin heavy chains and the constant region of IgG) and the custom-designed macro-self antigen that binds the constant region of Igκ immunoglobulin light chains.
- B1 cell
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A cell with the phenotype IgMhiIgDlow macrophage receptor 1 (MAC1)+B220low CD23−. These B cells are the main population of B cells found in the peritoneal and pleural cavities. Their precursors develop in the fetal liver and omentum. In adult mice, the B1-cell population is maintained at a constant size, owing to the self-renewing capacity of these cells. B1 cells recognize self components, as well as common bacterial antigens, and they secrete antibodies that tend to have low affinity and broad specificity.
- Non-template-encoded nucleotides
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(N nucleotides). Nucleotides that are not encoded by the DNA and are added at V–D (variable–diversity)-minigene-element junctions and D–J (diversity–joining)-minigene-element junctions, thereby introducing new amino acids at these junctions.
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Nemazee, D. Receptor editing in lymphocyte development and central tolerance. Nat Rev Immunol 6, 728–740 (2006). https://doi.org/10.1038/nri1939
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DOI: https://doi.org/10.1038/nri1939
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