RAGs and regulation of autoantibodies

Annual Review of Immunology

Volumn 22, Issue , 2004, Pages 485-501

  Jankovic, Mila ^a   Casellas, Rafael ^b   Yannoutsos, Nikos ^a   Wardemann, Hedda ^a   Nussenzweig, Michel C ^a  

^a ROCKEFELLER UNIVERSITY   (United States)

^b CALIFORNIA INSTITUTE OF TECHNOLOGY   (United States)

Author keywords

Antiself antibodies; B cell development; RAG1 and RAG2 expression; Receptor editing; Tolerance

Indexed keywords

AUTOANTIBODY; CD4 ANTIGEN; CD8 ANTIGEN; DNA; IMMUNOGLOBULIN HEAVY CHAIN; IMMUNOGLOBULIN LIGHT CHAIN; IMMUNOGLOBULIN M; INSULIN; LYMPHOCYTE ANTIGEN RECEPTOR; MESSENGER RNA; RAG1 PROTEIN; RAG2 PROTEIN; RECOMBINASE; SIGNAL PEPTIDE;

B LYMPHOCYTE; BONE MARROW CELL; CELL MATURATION; CORRELATION ANALYSIS; CROSS LINKING; DEMETHYLATION; DNA CLEAVAGE; ENZYME LINKED IMMUNOSORBENT ASSAY; GENE CONTROL; GENE DELETION; GENE EXPRESSION; GENE EXPRESSION REGULATION; GENE REPLACEMENT THERAPY; GENETIC RECOMBINATION; GENETIC TRANSCRIPTION; GENETIC VARIABILITY; HUMAN; IMMUNOREGULATION; NONHUMAN; PRIORITY JOURNAL; PROTEIN ASSEMBLY; PROTEIN EXPRESSION; REVIEW; T LYMPHOCYTE RECEPTOR GENE; THYMOCYTE; WILD TYPE;

EID: 2542485540     PISSN: 07320582     EISSN: None     Source Type: Book Series    
DOI: 10.1146/annurev.immunol.22.012703.104707     Document Type: Review

References (141)

1. Tonegawa S. 1983. Somatic generation of antibody diversity. Nature 302:575-81
2. Silverstein AM. 2001. Autoimmunity versus horror autotoxicus: the struggle for recognition. Nat. Immunol. 2:279-81
3. Burnet MF. 1959. The Clonal Selection Theory of Acquired Immunity. Cambridge, UK: Cambridge Univ. Press
4. Talmage DW. 1959. Tumor development in immunologically deficient nude mice after exposure to chemical carcinogens. Science 129:1643-48
5. Lederberg J. 1959. Genes and antibodies. Science 129:1649-53
6. Gay D, Saunders T, Camper S, Weigert M. 1993. Receptor editing: an approach by autoreactive B cells to escape tolerance. J. Exp. Med. 177:999-1008
7. Tiegs SL, Russell DM, Nemazee D. 1993. Receptor editing in self-reactive bone marrow B cells. J. Exp. Med. 177:1009-20
8. Nemazee DA, Burki K. 1989. Clonal deletion of B lymphocytes in a transgenic mouse bearing anti-MHC class I antibody genes. Nature 337:562-66
9. Goodnow CC, Crosbie J, Adelstein S, Lavoie TB, Smith-Gill SJ, et al. 1988. Altered immunoglobulin expression and functional silencing of self-reactive B lymphocytes in transgenic mice. Nature 334:676-82
10. Landsteiner K. 1936. The Specificity of Serological Reactions. New York: Dover
11. Sidman CL, Unanue ER. 1975. Receptor-mediated inactivation of early B lymphocytes. Nature 257:149-51
12. Teale JM, Klinman NR. 1980. Tolerance as an active process. Nature 288:385-87
13. Nossal GJ. 1983. Cellular mechanisms of immunologic tolerance. Annu. Rev. Immunol. 1:33-62
14. Allman DM, Ferguson SE, Lentz VM, Cancro MP. 1993. Peripheral B cell maturation. II. Heat-stable antigen (hi) splenic B cells are an immature developmental intermediate in the production of long-lived marrow-derived B cells. J. Immunol. 151:4431-44
15. Norvell A, Mandik L, Monroe JG. 1995. Engagement of the antigen-receptor on immature murine B lymphocytes results in death by apoptosis. J. Immunol. 154:4404-13
16. Rolink AG, Andersson J, Melchers F. 1998. Characterization of immature B cells by a novel monoclonal antibody, by turnover and by mitogen reactivity. Eur. J. Immunol. 28:3738-48
17. Forster I, Rajewsky K. 1990. 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 87:4781-84
18. Hao Z, Rajewsky K. 2001. Homeostasis of peripheral B cells in the absence of B cell influx from the bone marrow. J. Exp. Med. 194:1151-64
19. Raff MC, Owen JJ, Cooper MD, Lawton ARd, Megson M, et al. 1975. Differences in susceptibility of mature and immature mouse B lymphocytes to antiimmunoglobulin-induced immunoglobulin suppression in vitro. Possible implications for B-cell tolerance to self. J. Exp. Med. 142:1052-64
20. Gu H, Tarlinton D, Muller W, Rajewsky K, Forster I. 1991. Most peripheral B cells in mice are ligand selected. J. Exp. Med. 173:1357-71
21. Sandel PC, Monroe JG. 1999. Negative selection of immature B cells by receptor editing or deletion is determined by site of antigen encounter. Immunity 10:289-99
22. Wardemann H, Yurasov S, Schaefer A, Young JW, Meffre E, Nussenzweig MC. 2003. Predominant autoantibody production by early human B cell precursors. Science 301(5638):1374-77
23. Schatz DG, Oettinger MA, Baltimore D. 1989. The V(D)J recombination activating gene, RAG-1. Cell 59:1035-48
24. Oettinger MA, Schatz DG, Gorka C, Baltimore D. 1990. RAG-1 and RAG-2, adjacent genes that synergistically activate V(D)J recombination. Science 248:1517-23
25. McBlane JF, van Gent DC, Ramsden DA, Romeo C, Cuomo CA, et al. 1995. Cleavage at a V(D)J recombination signal requires only RAG1 and RAG2 proteins and occurs in two steps. Cell 83:387-95
26. Mombaerts P, Iacomini J, Johnson RS, Herrup K, Tonegawa S, et al. 1992. RAG-1-deficient mice have no mature B and T lymphocytes. Cell 68:869-77
27. Shinkai Y, Rathbun G, Lam KP, Oltz EM, Stewart V, et al. 1992. RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement. Cell 68:855-67
28. Schwarz K, Gauss GH, Ludwig L, Pannicke U, Li Z, et al. 1996. RAG mutations in human B cell-negative SCID. Science 274:97-99
29. Wilson A, Held W, MacDonald HR. 1994. Two waves of recombinase gene expression in developing thymocytes. J. Exp. Med. 179:1355-60
30. Grawunder U, Leu TM, Schatz DG, Werner A, Rolink AG, et al. 1995. Downregulation of RAG1 and RAG2 gene expression in preB cells after functional immunoglobulin heavy chain rearrangement. Immunity 3:601-8
31. Allman D, Li J, Hardy RR. 1999. Commitment to the B lymphoid lineage occurs before DH-JH recombination. J. Exp. Med. 189:735-40
32. Yu W, Misulovin Z, Suh H, Hardy RR, Jankovic M, et al. 1999. Coordinate regulation of RAG1 and RAG2 by cell type-specific DNA elements 5′ of RAG2. Science 285:1080-84
33. Igarashi H, Gregory SC, Yokota T, Sakaguchi N, Kincade PW. 2002. Transcription from the RAG1 locus marks the earliest lymphocyte progenitors in bone marrow. Immunity 17:117-30
34. Alt FW, Yancopoulos GD, Blackwell TK, Wood C, Thomas E, et al. 1984. Ordered rearrangement of immunoglobulin heavy chain variable region segments. EMBO J. 3:1209-19
35. Li YS, Hayakawa K, Hardy RR. 1993. The regulated expression of B lineage associated genes during B cell differentiation in bone marrow and fetal liver. J. Exp. Med. 178:951-60
36. Ehlich A, Martin V, Muller W, Rajewsky K. 1994. Analysis of the B-cell progenitor compartment at the level of single cells. Curr. Biol. 4:573-83
37. Nussenzweig MC, Shaw AC, Sinn E, Danner DB, Holmes KL, et al. 1987. Allelic exclusion in transgenic mice that express the membrane form of immunoglobulin mu. Science 236:816-19
38. Manz J, Denis K, Witte O, Brinster R, Storb U. 1988. Feedback inhibition of immunoglobulin gene rearrangement by membrane mu, but not by secreted mu heavy chains [published erratum appears in J. Exp. Med. 1989 June 1. 169(6):2269]. J. Exp. Med. 168:1363-81
39. Kitamura D, Rajewsky K. 1992. Targeted disruption of mu chain membrane exon causes loss of heavy-chain allelic exclusion. Nature 356:154-56
40. Melchers F, Rolink A, Grawunder U, Winkler TH, Karasuyama H, et al. 1995. Positive and negative selection events during B lymphopoiesis. Curr. Opin. Immunol. 7:214-27
41. Bassing CH, Swat W, Alt FW. 2002. The mechanism and regulation of chromosomal V(D)J recombination. Cell 109(Suppl.):S45-55
42. Chowdhury D, Sen R. 2001. Stepwise activation of the immunoglobulin mu heavy chain gene locus. EMBO J. 20:6394-403
43. Melchers F. 1995. The role of B cell and pre-B cell receptors in development and growth control of the B-lymphocyte lineage. In Immunoglobulin Genes, ed. T Honjo, FW Alt. pp. 33-56. London: London Academic Ltd. 3rd ed.
44. Monroe RJ, Seidl KJ, Gaertner F, Han S, Chen F, et al. 1999. RAG2:GFP knockin mice reveal novel aspects of RAG2 expression in primary and peripheral lymphoid tissues. Immunity 11:201-12
45. Li Z, Dordai DI, Lee J, Desiderio S. 1996. A conserved degradation signal regulates RAG-2 accumulation during cell division and links V(D)J recombination to the cell cycle. Immunity 5:575-89
46. Ehlich A, Schaal S, Gu H, Kitamura D, Muller W, et al. 1993. Immunoglobulin heavy and light chain genes rearrange independently at early stages of B cell development. Cell 72:695-704
47. Carsetti R, Kohler G, Lamers MC. 1995. Transitional B cells are the target of negative selection in the B cell compartment. J. Exp. Med. 181:2129-40
48. Melamed D, Benschop RJ, Cambier JC, Nemazee D. 1998. Developmental regulation of B lymphocyte immune tolerance compartmentalizes clonal selection from receptor selection. Cell 92:173-82
49. Radic MZ, Erikson J, Litwin S, Weigert M. 1993. B lymphocytes may escape tolerance by revising their antigen receptors. J. Exp. Med. 177:1165-73
50. Feddersen RM, Van Ness BG. 1985. Double recombination of a single immunoglobulin kappa-chain allele: implications for the mechanism of rearrangement. Proc. Natl. Acad. Sci. USA 82: 4793-97
51. Levy S, Campbell MJ, Levy R. 1989. Functional immunoglobulin light chain genes are replaced by ongoing rearrangements of germline V kappa genes to downstream J kappa segment in a murine B cell line. J. Exp. Med. 170:1-13
52. Kleinfield R, Hardy RR, Tarlinton D, Dangl J, Herzenberg LA, et al. 1986. Recombination between an expressed immunoglobulin heavy-chain gene and a germline variable gene segment in a Ly 1 + B-cell lymphoma. Nature 322:843-46
53. Ritchie KA, Brinster RL, Storb U. 1984. Allelic exclusion and control of endogenous immunoglobulin gene rearrangement in kappa transgenic mice. Nature 312:517-20
54. Rusconi S, Kohler G. 1985. Transmission and expression of a specific pair of rearranged immunoglobulin mu and kappa genes in a transgenic mouse line. Nature 314:330-34
55. Erikson J, Radic MZ, Camper SA, Hardy RR, Carmack C, et al. 1991. Expression of anti-DNA immunoglobulin transgenes in non-autoimmune mice. Nature 349:331-34
56. Prak EL, Trounstine M, Huszar D, Weigert M. 1994. Light chain editing in kappa-deficient animals: a potential mechanism of B cell tolerance. J. Exp. Med. 180:1805-15
57. Li H, Jiang Y, Prak EL, Radic M, Weigert M. 2001. Editors and editing of anti-DNA receptors. Immunity 15:947-57
58. Pelanda R, Schwers S, Sonoda E, Torres RM, Nemazee D, et al. 1997. Receptor editing in a transgenic mouse model: site, efficiency, and role in B cell tolerance and antibody diversification. Immunity 7:765-75
59. Chen C, Prak EL, Weigert M. 1997. Editing disease-associated autoantibodies. Immunity 6:97-105
60. Kleinfield RW, Weigert MG. 1989. Analysis of VH gene replacement events in a B cell lymphoma. J. Immunol. 142:4475-82
61. Reth M, Gehrmann P, Petrac E, Wiese P. 1986. A novel VH to VHDJH joining mechanism in heavy-chain-negative (null) pre-B cells results in heavy-chain production. Nature 322:840-42
62. Wilson PC, Wilson K, Liu YJ, Banchereau J, Pascual V, et al. 2000. Receptor revision of immunoglobulin heavy chain variable region genes in normal human B lymphocytes. J. Exp. Med. 191:1881-94
63. Chen C, Nagy Z, Prak EL, Weigert M. 1995. Immunoglobulin heavy chain gene replacement: a mechanism of receptor editing. Immunity 3:747-55
64. Pewzner-Jung Y, Friedmann D, Sonoda E, Jung S, Rajewsky K, et al. 1998. 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. 161:4634-45
65. Itoh K, Meffre E, Albesiano E, Farber A, Dines D, et al. 2000. Immunoglobulin heavy chain variable region gene replacement as a mechanism for receptor revision in rheumatoid arthritis synovial tissue B lymphocytes. J. Exp. Med. 192:1151-64
66. Sonoda E, Pewzner-Jung Y, Schwers S, Taki S, Jung S, et al. 1997. B cell development under the condition of allelic inclusion. Immunity 6:225-33
67. Cascalho M, Ma A, Lee S, Masat L, Wabl M. 1996. A quasi-monoclonal mouse. Science 272:1649-52
68. Zhang Z ZM, Wang YH, Munfus D, Huye LE, Findley HW, et al. 2003. Contribution of Vh gene replacement to the primary B cell repertoire. Immunity 19:21-31
69. Hertz M, Nemazee D. 1997. BCR ligation induces receptor editing in IgM+IgD-bone marrow B cells in vitro. Immunity 6:429-36
70. Melamed D, Nemazee D. 1997. Self-antigen does not accelerate immature B cell apoptosis, but stimulates receptor editing as a consequence of developmental arrest. Proc. Natl. Acad. Sci. USA 94:9267-72
71. Nemazee D, Buerki K. 1989. Clonal deletion of autoreactive B lymphocytes in bone marrow chimeras. Proc. Natl. Acad. Sci. USA 86:8039-43
72. Yu W, Nagaoka H, Jankovic M, Misulovin Z, Suh H, et al. 1999. Continued RAG expression in late stages of B cell development and no apparent re-induction after immunization. Nature 400:682-87
73. Casellas R, Shih TA, Kleinewietfeld M, Rakonjac J, Nemazee D, et al. 2001. Contribution of receptor editing to the antibody repertoire. Science 291:1541-44
74. Oberdoerffer P, Novobrantseva TI, Rajewsky K. 2003. Expression of a targeted lambda 1 light chain gene is developmentally regulated and independent of Ig kappa rearrangements. J. Exp. Med. 197:1165-72
75. Prak EL, Weigert M. 1995. Light chain replacement: a new model for antibody gene rearrangement. J. Exp. Med. 182:541-48
76. Brauninger A, Goossens T, Rajewsky K, Kuppers R. 2001. Regulation of immunoglobulin light chain gene rearrangements during early B cell development in the human. Eur. J. Immunol. 31:3631-37
77. Retter MW, Nemazee D. 1998. Receptor editing occurs frequently during normal B cell development. J. Exp. Med. 188:1231-38
78. Blackwell TK, Moore MW, Yancopoulos GD, Suh H, Lutzker S, et al. 1986. Recombination between immunoglobulin variable region gene segments is enhanced by transcription. Nature 324:585-89
79. Schlissel MS, Baltimore D. 1989. Activation of immunoglobulin kappa gene rearrangement correlates with induction of germline kappa gene transcription. Cell 58:1001-7
80. Yancopoulos GD, Alt FW. 1985. Developmentally controlled and tissue-specific expression of unrearranged VH gene segments. Cell 40:271-81
81. Chen J, Young F, Bottaro A, Stewart V, Smith RK, et al. 1993. Mutations of the intronic IgH enhancer and its flanking sequences differentially affect accessibility of the JH locus. EMBO J. 12:4635-45
82. Serwe M, Sablitzky F. 1993. V(D)J recombination in B cells is impaired but not blocked by targeted deletion of the immunoglobulin heavy chain intron en-hancer. EMBO J. 12:2321-27
83. Xu Y, Davidson L, Alt FW, Baltimore D. 1996. Deletion of the Ig kappa light chain intronic enhancer/matrix attachment region impairs but does not abolish V kappa J kappa rearrangement. Immunity 4:377-85
84. Whitehurst CE, Schlissel MS, Chen J. 2000. Deletion of germline promoter PD beta 1 from the TCR beta locus causes hypermethylation that impairs D beta 1 recombination by multiple mechanisms. Immunity 13:703-14
85. Corcoran AE, Riddell A, Krooshoop D, Venkitaraman AR. 1998. Impaired immunoglobulin gene rearrangement in mice lacking the IL-7 receptor. Nature 391:904-7
86. Romanow WJ, Langerak AW, Goebel P, Wolvers-Tettero IL, van Dongen JJ, et al. 2000. E2A and EBF act in synergy with the V(D)J recombinase to generate a diverse immunoglobulin repertoire in nonlymphoid cells. Mol. Cell 5:343-53
87. Alvarez JD, Anderson SJ, Loh DY. 1995. V(D)J recombination and allelic exclusion of a TCR beta-chain minilocus occurs in the absence of a functional promoter. J. Immunol. 155:1191-202
88. Okada A, Mendelsohn M, Alt F. 1994. Differential activation of transcription versus recombination of transgenic T cell receptor beta variable region gene segments in B and T lineage cells. J. Exp. Med. 180:261-72
89. Cherry SR, Baltimore D. 1999. Chromatin remodeling directly activates V(D)J recombination. Proc. Natl. Acad. Sci. USA 96:10788-93
90. Angelin-Duclos C, Calame K. 1998. Evidence that immunoglobulin VH-DJ recombination does not require germ line transcription of the recombining variable gene segment. Mol. Cell Biol. 18:6253-64
91. Hesslein DG, Pflugh DL, Chowdhury D, Bothwell AL, Sen R, et al. 2003. Pax5 is required for recombination of transcribed, acetylated, 5′ IgH V gene segments. Genes Dev. 17:37-42
92. Gstaiger M, Knoepfel L, Georgiev O, Schaffner W, Hovens CM. 1995. A B-cell coactivator of octamer-binding transcription factors. Nature 373:360-62
93. Strubin M, Newell JW, Matthias P. 1995. OBF-1, a novel B cell-specific coactivator that stimulates immunoglobulin promoter activity through association with octamer-binding proteins. Cell 80:497-506
94. Luo Y, Fujii H, Gerster T, Roeder RG. 1992. A novel B cell-derived coactivator potentiates the activation of immunoglobulin promoters by octamer-binding transcription factors. Cell 71:231-41
95. Staudt LM, Lenardo MJ. 1991. Immunoglobulin gene transcription. Annu. Rev. Immunol. 9:373-98
96. Luo Y, Roeder RG. 1995. Cloning, functional characterization, and mechanism of action of the B-cell-specific transcriptional coactivator OCA-B. Mol. Cell Biol. 15:4115-24
97. Schubart DB, Rolink A, Kosco-Vilbois MH, Botteri F, Matthias P. 1996. B-cell-specific coactivator OBF-1/OCA-B/Bob1 required for immune response and germinal centre formation. Nature 383:538-42
98. Casellas R, Jankovic M, Meyer G, Gazumyan A, Luo Y, et al. 2002. OcaB is required for normal transcription and V(D)J recombination of a subset of immunoglobulin κ genes. Cell 110:575-85
99. Han S, Zheng B, Schatz DG, Spanopoulou E, Kelsoe G. 1996. Neoteny in lymphocytes: Rag1 and Rag2 expression in germinal center B cells. Science 274:2094-97
100. Hikida M, Mori M, Takai T, Tomochika K, Hamatani K, et al. 1996. Reexpression of RAG-1 and RAG-2 genes in activated mature mouse B cells. Science 274:2092-94
101. Giachino C, Padovan E, Lanzavecchia A. 1998. Re-expression of RAG-1 RAG-2 genes and evidence for secondary rearrangements in human germinal center B lymphocytes. Eur. J. Immunol. 28:3506-13
102. Girschick HJ, Grammer AC, Nanki T, Mayo M, Lipsky PE. 2001. RAG1 and RAG2 expression by B cell subsets from human tonsil and peripheral blood. J. Immunol. 166:377-86
103. Hikida M, Ohmori H. 1998. Rearrangement of lambda light chain genes in mature B cells in vitro and in vivo. Function of reexpressed recombination-activating gene (RAG) products. J. Exp. Med. 187:795-99
104. Meffre E, Papavasiliou F, Cohen P, de Bouteiller O, Bell D, et al. 1998. Antigen receptor engagement turns off the V(D)J recombination machinery in human tonsil B cells. J. Exp. Med. 188:765-72
105. Meffre E, Davis E, Schiff C, Cunningham-Rundles C, Ivashkiv LB, et al. 2000. Circulating human B cells that express surrogate light chains edited receptors. Nat. Immunol. 1:207-13
106. Hikida M, Nakayama Y, Yamashita Y, Kumazawa Y, Nishikawa SI, et al. 1998. Expression of recombination activating genes in germinal center B cells: involvement of interleukin 7 (IL-7) and the IL-7 receptor. J. Exp. Med. 188:365-72
107. Papavasiliou F, Casellas R, Suh H, Qin XF, Besmer E, et al. 1997. V(D)J recombination in mature B cells: a mechanism for altering antibody responses. Science 278:298-301
108. Han S, Dillon SR, Zheng B, Shimoda M, Schlissel MS, et al. 1997. V(D)J recombinase activity in a subset of germinal center B lymphocytes. Science 278:301-5
109. Gartner F, Alt FW, Monroe RJ, Seidl KJ. 2000. Antigen-independent appearance of recombination activating gene (RAG)-positive bone marrow B cells in the spleens of immunized mice. J. Exp. Med. 192:1745-54
110. Nagaoka H, Gonzalez-Aseguinolaza G, Tsuji M, Nussenzweig MC. 2000. 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. 191:2113-20
111. Lawton AR 3rd, Asofsky R, Hylton MB, Cooper MD. 1972. Suppression of immunoglobulin class synthesis in mice. I. Effects of treatment with antibody to μ-chain. J. Exp. Med. 135:277-97
112. Chen C, Nagy Z, Radic MZ, Hardy RR, Huszar D, et al. 1995. The site and stage of anti-DNA B-cell deletion. Nature 373:252-55
113. Hartley SB, Cooke MP, Fulcher DA, Harris AW, Cory S, et al. 1993. Elimination of self-reactive B lymphocytes proceeds in two stages: arrested development and cell death. Cell 72:325-35
114. Okamoto M, Murakami M, Shimizu A, Ozaki S, Tsubata T, et al. 1992. A transgenic model of autoimmune hemolytic anemia. J. Exp. Med. 175:71-79
115. Spanopoulou E, Roman CA, Corcoran LM, Schlissel MS, Silver DP, et al. 1994. Functional immunoglobulin transgenes guide ordered B-cell differentiation in Rag-1-deficient mice. Genes Dev. 8:1030-42
116. Xu H, Li H, Suri-Payer E, Hardy RR, Weigert M. 1998. Regulation of anti-DNA B cells in recombination-activating gene-deficient mice. J. Exp. Med. 188:1247-54
117. Sandel PC, Gendelman M, Kelsoe G, Monroe JG. 2001. Definition of a novel cellular constituent of the bone marrow that regulates the response of immature B cells to B cell antigen receptor engagement. J. Immunol. 166:5935-44
118. Fugmann SD, Lee AI, Shockett PE, Villey LT, Schatz DG. 2000. The RAG proteins and V(D)J recombination: complexes, ends, and transposition. Annu. Rev. Immunol. 18:495-527
119. Flajnik MF. 1998. Churchill and the immune system of ectothermic vertebrates. Immunol. Rev. 166:5-14
120. Hiom K, Melek M, Gellert M. 1998. DNA transposition by the RAG1 and RAG2 proteins: a possible source of oncogenic translocations. Cell 94:463-70
121. Agrawal A, Eastman QM, Schatz DG. 1998. Transposition mediated by RAG1 and RAG2 and its implications for the evolution of the immune system. Nature 394:744-51
122. Zarrin AA, Fong I, Malkin L, Marsden PA, Berinstein NL. 1997. Cloning and characterization of the human recombination activating gene 1 (RAG1) and RAG2 promoter regions. J. Immunol. 159:4382-94
123. Kurioka H, Kishi H, Isshiki H, Tagoh H, Mori K, et al. 1996. Isolation and characterization of a TATA-less promoter for the human RAG-1 gene. Mol. Immunol. 33:1059-66
124. Kitagawa T, Mori K, Kishi H, Tagoh H, Nagata T, et al. 1996. Chromatin structure and transcriptional regulation of human RAG-1 gene. Blood 88:3785-91
125. Fuller K, Storb U. 1997. Identification and characterization of the murine Rag1 promoter. Mol. Immunol. 34:939-54
126. Brown ST, Miranda GA, Galic Z, Hartman IZ, Lyon CJ, et al. 1997. Regulation of the RAG-1 promoter by the NF-Y transcription factor. J. Immunol. 158:5071-74
127. Lauring J, Schlissel MS. 1999. Distinct factors regulate the murine RAG-2 promoter in B- and T-cell lines. Mol. Cell. Biol. 19:2601-12
128. Kishi H, Wei XC, Jin ZX, Fujishiro Y, Nagata T, et al. 2000. Lineage-specific regulation of the murine RAG-2 promoter: GATA-3 in T cells and Pax-5 in B cells. Blood 95:3845-52
129. Hsu LY, Lauring J, Liang HE, Greenbaum S, Cado D, et al. 2003. A conserved transcriptional enhancer regulates RAG gene expression in developing B cells. Immunity 19:105-17
130. Monroe RJ, Chen F, Ferrini R, Davidson L, Alt FW. 1999. RAG2 is regulated differentially in B and T cells by elements 5′ of the promoter. Proc. Natl. Acad. Sci. USA 96:12713-18
131. Yannoutsos N, Wilson P, Yu W, Chen HT, Nussenzweig A, et al. 2001. The role of recombination activating gene (RAG) reinduction in thymocyte development in vivo. J. Exp. Med. 194:471-80
132. Grosveld F, van Assendelft GB, Greaves DR, Kollias G. 1987. Position-independent, high-level expression of the human beta-globin gene in transgenic mice. Cell 51:975-85
133. Li Q, Peterson KR, Fang X, Stamatoyannopoulos G. 2002. Locus control regions. Blood 100:3077-86
134. Godfrey D, Kennedy J, Mombaerts P, Tonegawa S, Zlotnik A. 1994. Onset of TCR-beta gene rearrangement and role of TCR-beta expression during CD3-CD4-CD8-thymocyte differentiation. J. Immunol. 152:4783-92
135. von Boehmer H, Fehling HJ. 1997. Structure and function of the pre-T cell receptor. Annu. Rev. Immunol. 15:433-52
136. Kruisbeek AM, Haks MC, Carleton M, Wiest DL, Michie AM, et al. 2000. Branching out to gain control: how the pre-TCR is linked to multiple functions. Immunol. Today 21:637-44
137. Petrie H, Livak F, Schatz D, Strasser A, Crispe I, et al. 1993. Multiple rearrangements in T cell receptor alpha chain genes maximize the production of useful thymocytes. J. Exp. Med. 178:615-22
138. Shinkai Y, Koyasu S, Nakayama K, Murphy KM, Loh DY, et al. 1993. Restoration of T cell development in RAG-2-deficient mice by functional TCR transgenes. Science 259:822-25
139. Guo J, Hawwari A, Li H, Sun Z, Mahanta SK, et al. 2002. Regulation of the TCRalpha repertoire by the survival window of CD4(+)CD8(+) thymocytes. Nat. Immunol. 3:469-76
140. Turka LA, Schatz DG, Oettinger MA, Chun JJ, Gorka C, et al. 1991. Thymocyte expression of RAG-1 and RAG-2: termination by T cell receptor cross-linking. Science 16:778-81
141. Borgulya P, Kishi H, Uematsu Y, von Boehmer H. 1992. Exclusion and inclusion of α and β T cell receptor alleles. Cell 69:529-37