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. 1993 Mar 1;177(3):729–739. doi: 10.1084/jem.177.3.729

Ordered rearrangement of variable region genes of the T cell receptor gamma locus correlates with transcription of the unrearranged genes

PMCID: PMC2190937  PMID: 8382255

Abstract

T cell receptor V gamma genes rearrange to the J gamma 1 gene segment in a highly ordered fashion during development. We demonstrate a striking correlation between the pattern of expression of unrearranged V gamma genes and the timing of their rearrangement. Thus, the increases in V gamma 2 rearrangements, and decreases in V gamma 3 and V gamma 4 rearrangements observed during development are paralleled by increasing or decreasing levels of the corresponding unrearranged V gene transcript. We also provide evidence that both the V gamma 3 and V gamma 4 genes are accessible in mature V gamma 3+ cells, but that the V gamma 4 gene may be inaccessible in the progenitors of V gamma 3 cells. The results suggest that regulated local accessibility of the chromatin surrounding V gamma genes is responsible for ordered V gamma gene rearrangement during development.

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Selected References

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  1. Aguilar L. K., Belmont J. W. V gamma 3 T cell receptor rearrangement and expression in the adult thymus. J Immunol. 1991 Feb 15;146(4):1348–1352. [PubMed] [Google Scholar]
  2. Allison J. P., Havran W. L. The immunobiology of T cells with invariant gamma delta antigen receptors. Annu Rev Immunol. 1991;9:679–705. doi: 10.1146/annurev.iy.09.040191.003335. [DOI] [PubMed] [Google Scholar]
  3. Alt F. W., Blackwell T. K., DePinho R. A., Reth M. G., Yancopoulos G. D. Regulation of genome rearrangement events during lymphocyte differentiation. Immunol Rev. 1986 Feb;89:5–30. doi: 10.1111/j.1600-065x.1986.tb01470.x. [DOI] [PubMed] [Google Scholar]
  4. Asarnow D. M., Kuziel W. A., Bonyhadi M., Tigelaar R. E., Tucker P. W., Allison J. P. Limited diversity of gamma delta antigen receptor genes of Thy-1+ dendritic epidermal cells. Cell. 1988 Dec 2;55(5):837–847. doi: 10.1016/0092-8674(88)90139-0. [DOI] [PubMed] [Google Scholar]
  5. Bonneville M., Ito K., Krecko E. G., Itohara S., Kappes D., Ishida I., Kanagawa O., Janeway C. A., Murphy D. B., Tonegawa S. Recognition of a self major histocompatibility complex TL region product by gamma delta T-cell receptors. Proc Natl Acad Sci U S A. 1989 Aug;86(15):5928–5932. doi: 10.1073/pnas.86.15.5928. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Brenner M. B., Strominger J. L., Krangel M. S. The gamma delta T cell receptor. Adv Immunol. 1988;43:133–192. [PubMed] [Google Scholar]
  7. Carding S. R., Kyes S., Jenkinson E. J., Kingston R., Bottomly K., Owen J. J., Hayday A. C. Developmentally regulated fetal thymic and extrathymic T-cell receptor gamma delta gene expression. Genes Dev. 1990 Aug;4(8):1304–1315. doi: 10.1101/gad.4.8.1304. [DOI] [PubMed] [Google Scholar]
  8. Chien Y. H., Iwashima M., Wettstein D. A., Kaplan K. B., Elliott J. F., Born W., Davis M. M. T-cell receptor delta gene rearrangements in early thymocytes. Nature. 1987 Dec 24;330(6150):722–727. doi: 10.1038/330722a0. [DOI] [PubMed] [Google Scholar]
  9. Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
  10. Chou H. S., Anderson S. J., Louie M. C., Godambe S. A., Pozzi M. R., Behlke M. A., Huppi K., Loh D. Y. Tandem linkage and unusual RNA splicing of the T-cell receptor beta-chain variable-region genes. Proc Natl Acad Sci U S A. 1987 Apr;84(7):1992–1996. doi: 10.1073/pnas.84.7.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Cron R. Q., Ezquerra A., Coligan J. E., Houlden B. A., Bluestone J. A., Maloy W. L. Identification of distinct T cell receptor (TCR)-gamma delta heterodimers using an anti-TCR-gamma variable region serum. J Immunol. 1989 Dec 1;143(11):3769–3775. [PubMed] [Google Scholar]
  12. Cron R. Q., Koning F., Maloy W. L., Pardoll D., Coligan J. E., Bluestone J. A. Peripheral murine CD3+, CD4-, CD8- T lymphocytes express novel T cell receptor gamma delta structures. J Immunol. 1988 Aug 15;141(4):1074–1082. [PubMed] [Google Scholar]
  13. Dialynas D. P., Wilde D. B., Marrack P., Pierres A., Wall K. A., Havran W., Otten G., Loken M. R., Pierres M., Kappler J. Characterization of the murine antigenic determinant, designated L3T4a, recognized by monoclonal antibody GK1.5: expression of L3T4a by functional T cell clones appears to correlate primarily with class II MHC antigen-reactivity. Immunol Rev. 1983;74:29–56. doi: 10.1111/j.1600-065x.1983.tb01083.x. [DOI] [PubMed] [Google Scholar]
  14. Elliott J. F., Rock E. P., Patten P. A., Davis M. M., Chien Y. H. The adult T-cell receptor delta-chain is diverse and distinct from that of fetal thymocytes. Nature. 1988 Feb 18;331(6157):627–631. doi: 10.1038/331627a0. [DOI] [PubMed] [Google Scholar]
  15. Engler P., Roth P., Kim J. Y., Storb U. Factors affecting the rearrangement efficiency of an Ig test gene. J Immunol. 1991 Apr 15;146(8):2826–2835. [PubMed] [Google Scholar]
  16. Ferrier P., Krippl B., Blackwell T. K., Furley A. J., Suh H., Winoto A., Cook W. D., Hood L., Costantini F., Alt F. W. Separate elements control DJ and VDJ rearrangement in a transgenic recombination substrate. EMBO J. 1990 Jan;9(1):117–125. doi: 10.1002/j.1460-2075.1990.tb08087.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Fondell J. D., Marcu K. B. Transcription of germ line V alpha segments correlates with ongoing T-cell receptor alpha-chain rearrangement. Mol Cell Biol. 1992 Apr;12(4):1480–1489. doi: 10.1128/mcb.12.4.1480. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Garman R. D., Doherty P. J., Raulet D. H. Diversity, rearrangement, and expression of murine T cell gamma genes. Cell. 1986 Jun 6;45(5):733–742. doi: 10.1016/0092-8674(86)90787-7. [DOI] [PubMed] [Google Scholar]
  19. Havran W. L., Allison J. P. Developmentally ordered appearance of thymocytes expressing different T-cell antigen receptors. Nature. 1988 Sep 29;335(6189):443–445. doi: 10.1038/335443a0. [DOI] [PubMed] [Google Scholar]
  20. Havran W. L., Chien Y. H., Allison J. P. Recognition of self antigens by skin-derived T cells with invariant gamma delta antigen receptors. Science. 1991 Jun 7;252(5011):1430–1432. doi: 10.1126/science.1828619. [DOI] [PubMed] [Google Scholar]
  21. Havran W. L., Grell S., Duwe G., Kimura J., Wilson A., Kruisbeek A. M., O'Brien R. L., Born W., Tigelaar R. E., Allison J. P. Limited diversity of T-cell receptor gamma-chain expression of murine Thy-1+ dendritic epidermal cells revealed by V gamma 3-specific monoclonal antibody. Proc Natl Acad Sci U S A. 1989 Jun;86(11):4185–4189. doi: 10.1073/pnas.86.11.4185. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Heilig J. S., Tonegawa S. Diversity of murine gamma genes and expression in fetal and adult T lymphocytes. 1986 Aug 28-Sep 3Nature. 322(6082):836–840. doi: 10.1038/322836a0. [DOI] [PubMed] [Google Scholar]
  23. Holsti M. A., Raulet D. H. IL-6 and IL-1 synergize to stimulate IL-2 production and proliferation of peripheral T cells. J Immunol. 1989 Oct 15;143(8):2514–2519. [PubMed] [Google Scholar]
  24. Houlden B. A., Cron R. Q., Coligan J. E., Bluestone J. A. Systematic development of distinct T cell receptor-gamma delta T cell subsets during fetal ontogeny. J Immunol. 1988 Dec 1;141(11):3753–3759. [PubMed] [Google Scholar]
  25. Hsieh C. L., Lieber M. R. CpG methylated minichromosomes become inaccessible for V(D)J recombination after undergoing replication. EMBO J. 1992 Jan;11(1):315–325. doi: 10.1002/j.1460-2075.1992.tb05054.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Hsieh C. L., McCloskey R. P., Lieber M. R. V(D)J recombination on minichromosomes is not affected by transcription. J Biol Chem. 1992 Aug 5;267(22):15613–15619. [PubMed] [Google Scholar]
  27. Ikuta K., Kina T., MacNeil I., Uchida N., Peault B., Chien Y. H., Weissman I. L. A developmental switch in thymic lymphocyte maturation potential occurs at the level of hematopoietic stem cells. Cell. 1990 Sep 7;62(5):863–874. doi: 10.1016/0092-8674(90)90262-d. [DOI] [PubMed] [Google Scholar]
  28. Ito K., Bonneville M., Takagaki Y., Nakanishi N., Kanagawa O., Krecko E. G., Tonegawa S. Different gamma delta T-cell receptors are expressed on thymocytes at different stages of development. Proc Natl Acad Sci U S A. 1989 Jan;86(2):631–635. doi: 10.1073/pnas.86.2.631. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Itohara S., Farr A. G., Lafaille J. J., Bonneville M., Takagaki Y., Haas W., Tonegawa S. Homing of a gamma delta thymocyte subset with homogeneous T-cell receptors to mucosal epithelia. Nature. 1990 Feb 22;343(6260):754–757. doi: 10.1038/343754a0. [DOI] [PubMed] [Google Scholar]
  30. Itohara S., Nakanishi N., Kanagawa O., Kubo R., Tonegawa S. Monoclonal antibodies specific to native murine T-cell receptor gamma delta: analysis of gamma delta T cells during thymic ontogeny and in peripheral lymphoid organs. Proc Natl Acad Sci U S A. 1989 Jul;86(13):5094–5098. doi: 10.1073/pnas.86.13.5094. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Itohara S., Tonegawa S. Selection of gamma delta T cells with canonical T-cell antigen receptors in fetal thymus. Proc Natl Acad Sci U S A. 1990 Oct;87(20):7935–7938. doi: 10.1073/pnas.87.20.7935. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Kappes D. J., Browne C. P., Tonegawa S. Identification of a T-cell-specific enhancer at the locus encoding T-cell antigen receptor gamma chain. Proc Natl Acad Sci U S A. 1991 Mar 15;88(6):2204–2208. doi: 10.1073/pnas.88.6.2204. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Korman A. J., Marusic-Galesic S., Spencer D., Kruisbeek A. M., Raulet D. H. Predominant variable region gene usage by gamma/delta T cell receptor-bearing cells in the adult thymus. J Exp Med. 1988 Sep 1;168(3):1021–1040. doi: 10.1084/jem.168.3.1021. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Kuziel W. A., Takashima A., Bonyhadi M., Bergstresser P. R., Allison J. P., Tigelaar R. E., Tucker P. W. Regulation of T-cell receptor gamma-chain RNA expression in murine Thy-1+ dendritic epidermal cells. Nature. 1987 Jul 16;328(6127):263–266. doi: 10.1038/328263a0. [DOI] [PubMed] [Google Scholar]
  35. Kyes S., Carew E., Carding S. R., Janeway C. A., Jr, Hayday A. Diversity in T-cell receptor gamma gene usage in intestinal epithelium. Proc Natl Acad Sci U S A. 1989 Jul;86(14):5527–5531. doi: 10.1073/pnas.86.14.5527. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Lafaille J. J., DeCloux A., Bonneville M., Takagaki Y., Tonegawa S. Junctional sequences of T cell receptor gamma delta genes: implications for gamma delta T cell lineages and for a novel intermediate of V-(D)-J joining. Cell. 1989 Dec 1;59(5):859–870. doi: 10.1016/0092-8674(89)90609-0. [DOI] [PubMed] [Google Scholar]
  37. Lennon G. G., Perry R. P. The temporal order of appearance of transcripts from unrearranged and rearranged Ig genes in murine fetal liver. J Immunol. 1990 Mar 1;144(5):1983–1987. [PubMed] [Google Scholar]
  38. Lutzker S., Rothman P., Pollock R., Coffman R., Alt F. W. Mitogen- and IL-4-regulated expression of germ-line Ig gamma 2b transcripts: evidence for directed heavy chain class switching. Cell. 1988 Apr 22;53(2):177–184. doi: 10.1016/0092-8674(88)90379-0. [DOI] [PubMed] [Google Scholar]
  39. Malynn B. A., Yancopoulos G. D., Barth J. E., Bona C. A., Alt F. W. Biased expression of JH-proximal VH genes occurs in the newly generated repertoire of neonatal and adult mice. J Exp Med. 1990 Mar 1;171(3):843–859. doi: 10.1084/jem.171.3.843. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Martin D., Huang R. Q., LeBien T., Van Ness B. Induced rearrangement of kappa genes in the BLIN-1 human pre-B cell line correlates with germline J-C kappa and V kappa transcription. J Exp Med. 1991 Mar 1;173(3):639–645. doi: 10.1084/jem.173.3.639. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Matis L. A., Fry A. M., Cron R. Q., Cotterman M. M., Dick R. F., Bluestone J. A. Structure and specificity of a class II MHC alloreactive gamma delta T cell receptor heterodimer. Science. 1989 Aug 18;245(4919):746–749. doi: 10.1126/science.2528206. [DOI] [PubMed] [Google Scholar]
  42. Melton D. A., Krieg P. A., Rebagliati M. R., Maniatis T., Zinn K., Green M. R. Efficient in vitro synthesis of biologically active RNA and RNA hybridization probes from plasmids containing a bacteriophage SP6 promoter. Nucleic Acids Res. 1984 Sep 25;12(18):7035–7056. doi: 10.1093/nar/12.18.7035. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Nandi D., Allison J. P. Phenotypic analysis and gamma delta-T cell receptor repertoire of murine T cells associated with the vaginal epithelium. J Immunol. 1991 Sep 15;147(6):1773–1778. [PubMed] [Google Scholar]
  44. Raulet D. H., Gottlieb P. D., Bevan M. J. Fractionation of lymphocyte populations with monoclonal antibodies specific for LYT-2.2 and LYT-3.1. J Immunol. 1980 Sep;125(3):1136–1143. [PubMed] [Google Scholar]
  45. Raulet D. H., Spencer D. M., Hsiang Y. H., Goldman J. P., Bix M., Liao N. S., Zijstra M., Jaenisch R., Correa I. Control of gamma delta T-cell development. Immunol Rev. 1991 Apr;120:185–204. doi: 10.1111/j.1600-065x.1991.tb00592.x. [DOI] [PubMed] [Google Scholar]
  46. Raulet D. H. The structure, function, and molecular genetics of the gamma/delta T cell receptor. Annu Rev Immunol. 1989;7:175–207. doi: 10.1146/annurev.iy.07.040189.001135. [DOI] [PubMed] [Google Scholar]
  47. Saiki R. K., Gelfand D. H., Stoffel S., Scharf S. J., Higuchi R., Horn G. T., Mullis K. B., Erlich H. A. Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science. 1988 Jan 29;239(4839):487–491. doi: 10.1126/science.2448875. [DOI] [PubMed] [Google Scholar]
  48. Schlissel M. S., Baltimore D. Activation of immunoglobulin kappa gene rearrangement correlates with induction of germline kappa gene transcription. Cell. 1989 Sep 8;58(5):1001–1007. doi: 10.1016/0092-8674(89)90951-3. [DOI] [PubMed] [Google Scholar]
  49. Schroeder H. W., Jr, Hillson J. L., Perlmutter R. M. Early restriction of the human antibody repertoire. Science. 1987 Nov 6;238(4828):791–793. doi: 10.1126/science.3118465. [DOI] [PubMed] [Google Scholar]
  50. Schroeder H. W., Jr, Walter M. A., Hofker M. H., Ebens A., Willems van Dijk K., Liao L. C., Cox D. W., Milner E. C., Perlmutter R. M. Physical linkage of a human immunoglobulin heavy chain variable region gene segment to diversity and joining region elements. Proc Natl Acad Sci U S A. 1988 Nov;85(21):8196–8200. doi: 10.1073/pnas.85.21.8196. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Spencer D. M., Hsiang Y. H., Goldman J. P., Raulet D. H. Identification of a T-cell-specific transcriptional enhancer located 3' of C gamma 1 in the murine T-cell receptor gamma locus. Proc Natl Acad Sci U S A. 1991 Feb 1;88(3):800–804. doi: 10.1073/pnas.88.3.800. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Stavnezer J., Radcliffe G., Lin Y. C., Nietupski J., Berggren L., Sitia R., Severinson E. Immunoglobulin heavy-chain switching may be directed by prior induction of transcripts from constant-region genes. Proc Natl Acad Sci U S A. 1988 Oct;85(20):7704–7708. doi: 10.1073/pnas.85.20.7704. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Takagaki Y., DeCloux A., Bonneville M., Tonegawa S. Diversity of gamma delta T-cell receptors on murine intestinal intra-epithelial lymphocytes. Nature. 1989 Jun 29;339(6227):712–714. doi: 10.1038/339712a0. [DOI] [PubMed] [Google Scholar]
  54. Wells F. B., Gahm S. J., Hedrick S. M., Bluestone J. A., Dent A., Matis L. A. Requirement for positive selection of gamma delta receptor-bearing T cells. Science. 1991 Aug 23;253(5022):903–905. doi: 10.1126/science.1831565. [DOI] [PubMed] [Google Scholar]
  55. Yancopoulos G. D., Alt F. W. Developmentally controlled and tissue-specific expression of unrearranged VH gene segments. Cell. 1985 Feb;40(2):271–281. doi: 10.1016/0092-8674(85)90141-2. [DOI] [PubMed] [Google Scholar]
  56. Yancopoulos G. D., Desiderio S. V., Paskind M., Kearney J. F., Baltimore D., Alt F. W. Preferential utilization of the most JH-proximal VH gene segments in pre-B-cell lines. Nature. 1984 Oct 25;311(5988):727–733. doi: 10.1038/311727a0. [DOI] [PubMed] [Google Scholar]
  57. Yancopoulos G. D., Malynn B. A., Alt F. W. Developmentally regulated and strain-specific expression of murine VH gene families. J Exp Med. 1988 Jul 1;168(1):417–435. doi: 10.1084/jem.168.1.417. [DOI] [PMC free article] [PubMed] [Google Scholar]

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