Abstract
Based on the analysis of V alpha gene segment deletions in a panel of T lymphomas, we have constructed a map of the mouse T cell receptor alpha/delta region and assigned the relative position of 72 distinct V gene segments. Three major observations have emerged from such studies. First, members of a given V alpha subfamily are not organized in discrete units along the chromosome but largely interspersed with members of other V alpha subfamilies. Second, analysis of the deletion map suggests the existence of repetitive patterns (V alpha clusters) in the chromosomal distribution of the V alpha gene segments. Third, the present-day organization of the V alpha/delta region may be readily explained by a series of sequential duplications involving three ancestral V alpha clusters. Direct evidence for the existence of these unique structural features has been gained by cloning approximately 370 kb of DNA and positioning 26 distinct V alpha gene segments belonging to six different subfamilies. Finally, the relationships existing between the V alpha/delta gene segment organization and usage are discussed in terms of position-dependent models.
Full text
PDF









Images in this article
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Alt F. W., Blackwell T. K., Yancopoulos G. D. Development of the primary antibody repertoire. Science. 1987 Nov 20;238(4830):1079–1087. doi: 10.1126/science.3317825. [DOI] [PubMed] [Google Scholar]
- Arden B., Klotz J. L., Siu G., Hood L. E. Diversity and structure of genes of the alpha family of mouse T-cell antigen receptor. 1985 Aug 29-Sep 4Nature. 316(6031):783–787. doi: 10.1038/316783a0. [DOI] [PubMed] [Google Scholar]
- Becker D. M., Pattern P., Chien Y., Yokota T., Eshhar Z., Giedlin M., Gascoigne N. R., Goodnow C., Wolf R., Arai K. Variability and repertoire size of T-cell receptor V alpha gene segments. Nature. 1985 Oct 3;317(6036):430–434. doi: 10.1038/317430a0. [DOI] [PubMed] [Google Scholar]
- Berman J. E., Mellis S. J., Pollock R., Smith C. L., Suh H., Heinke B., Kowal C., Surti U., Chess L., Cantor C. R. Content and organization of the human Ig VH locus: definition of three new VH families and linkage to the Ig CH locus. EMBO J. 1988 Mar;7(3):727–738. doi: 10.1002/j.1460-2075.1988.tb02869.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Blankenstein T., Krawinkel U. Immunoglobulin VH region genes of the mouse are organized in overlapping clusters. Eur J Immunol. 1987 Sep;17(9):1351–1357. doi: 10.1002/eji.1830170920. [DOI] [PubMed] [Google Scholar]
- Bluestone J. A., Cron R. Q., Cotterman M., Houlden B. A., Matis L. A. Structure and specificity of T cell receptor gamma/delta on major histocompatibility complex antigen-specific CD3+, CD4-, CD8- T lymphocytes. J Exp Med. 1988 Nov 1;168(5):1899–1916. doi: 10.1084/jem.168.5.1899. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bonneville M., Ishida I., Mombaerts P., Katsuki M., Verbeek S., Berns A., Tonegawa S. Blockage of alpha beta T-cell development by TCR gamma delta transgenes. Nature. 1989 Dec 21;342(6252):931–934. doi: 10.1038/342931a0. [DOI] [PubMed] [Google Scholar]
- Brodeur P. H., Osman G. E., Mackle J. J., Lalor T. M. The organization of the mouse Igh-V locus. Dispersion, interspersion, and the evolution of VH gene family clusters. J Exp Med. 1988 Dec 1;168(6):2261–2278. doi: 10.1084/jem.168.6.2261. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Brodeur P. H., Riblet R. The immunoglobulin heavy chain variable region (Igh-V) locus in the mouse. I. One hundred Igh-V genes comprise seven families of homologous genes. Eur J Immunol. 1984 Oct;14(10):922–930. doi: 10.1002/eji.1830141012. [DOI] [PubMed] [Google Scholar]
- Chien Y. H., Iwashima M., Kaplan K. B., Elliott J. F., Davis M. M. A new T-cell receptor gene located within the alpha locus and expressed early in T-cell differentiation. 1987 Jun 25-Jul 1Nature. 327(6124):677–682. doi: 10.1038/327677a0. [DOI] [PubMed] [Google Scholar]
- 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]
- Chou H. S., Behlke M. A., Godambe S. A., Russell J. H., Brooks C. G., Loh D. Y. T cell receptor genes in an alloreactive CTL clone: implications for rearrangement and germline diversity of variable gene segments. EMBO J. 1986 Sep;5(9):2149–2155. doi: 10.1002/j.1460-2075.1986.tb04478.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Davis M. M., Bjorkman P. J. T-cell antigen receptor genes and T-cell recognition. Nature. 1988 Aug 4;334(6181):395–402. doi: 10.1038/334395a0. [DOI] [PubMed] [Google Scholar]
- 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]
- Feinberg A. P., Vogelstein B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem. 1983 Jul 1;132(1):6–13. doi: 10.1016/0003-2697(83)90418-9. [DOI] [PubMed] [Google Scholar]
- Frischauf A. M., Lehrach H., Poustka A., Murray N. Lambda replacement vectors carrying polylinker sequences. J Mol Biol. 1983 Nov 15;170(4):827–842. doi: 10.1016/s0022-2836(83)80190-9. [DOI] [PubMed] [Google Scholar]
- Fujimoto S., Yamagishi H. Isolation of an excision product of T-cell receptor alpha-chain gene rearrangements. Nature. 1987 May 21;327(6119):242–243. doi: 10.1038/327242a0. [DOI] [PubMed] [Google Scholar]
- Happ M. P., Kubo R. T., Palmer E., Born W. K., O'Brien R. L. Limited receptor repertoire in a mycobacteria-reactive subset of gamma delta T lymphocytes. Nature. 1989 Dec 7;342(6250):696–698. doi: 10.1038/342696a0. [DOI] [PubMed] [Google Scholar]
- Happ M. P., Palmer E. Thymocyte development: an analysis of T cell receptor gene expression in 519 newborn thymocyte hybridomas. Eur J Immunol. 1989 Jul;19(7):1317–1325. doi: 10.1002/eji.1830190725. [DOI] [PubMed] [Google Scholar]
- Iwashima M., Green A., Davis M. M., Chien Y. H. Variable region (V delta) gene segment most frequently utilized in adult thymocytes is 3' of the constant (C delta) region. Proc Natl Acad Sci U S A. 1988 Nov;85(21):8161–8165. doi: 10.1073/pnas.85.21.8161. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jouvin-Marche E., Morgado M. G., Trede N., Marche P. N., Couez D., Hue I., Gris C., Malissen M., Cazenave P. A. Complexity, polymorphism, and recombination of mouse T-cell receptor alpha gene families. Immunogenetics. 1989;30(2):99–104. doi: 10.1007/BF02421537. [DOI] [PubMed] [Google Scholar]
- Klotz J. L., Barth R. K., Kiser G. L., Hood L. E., Kronenberg M. Restriction fragment length polymorphisms of the mouse T-cell receptor gene families. Immunogenetics. 1989;29(3):191–201. doi: 10.1007/BF00373645. [DOI] [PubMed] [Google Scholar]
- 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]
- Korman A. J., Maruyama J., Raulet D. H. Rearrangement by inversion of a T-cell receptor delta variable region gene located 3' of the delta constant region gene. Proc Natl Acad Sci U S A. 1989 Jan;86(1):267–271. doi: 10.1073/pnas.86.1.267. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Koseki H., Imai K., Ichikawa T., Hayata I., Taniguchi M. Predominant use of a particular alpha-chain in suppressor T cell hybridomas specific for keyhole limpet hemocyanin. Int Immunol. 1989;1(6):557–564. doi: 10.1093/intimm/1.6.557. [DOI] [PubMed] [Google Scholar]
- Letourneur F., Malissen B. Derivation of a T cell hybridoma variant deprived of functional T cell receptor alpha and beta chain transcripts reveals a nonfunctional alpha-mRNA of BW5147 origin. Eur J Immunol. 1989 Dec;19(12):2269–2274. doi: 10.1002/eji.1830191214. [DOI] [PubMed] [Google Scholar]
- Lindsten T., Fowlkes B. J., Samelson L. E., Davis M. M., Chien Y. H. Transient rearrangements of the T cell antigen receptor alpha locus in early thymocytes. J Exp Med. 1987 Sep 1;166(3):761–775. doi: 10.1084/jem.166.3.761. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lötscher E., Grzeschik K. H., Bauer H. G., Pohlenz H. D., Straubinger B., Zachau H. G. Dispersed human immunoglobulin kappa light-chain genes. Nature. 1986 Apr 3;320(6061):456–458. doi: 10.1038/320456a0. [DOI] [PubMed] [Google Scholar]
- Malissen M., McCoy C., Blanc D., Trucy J., Devaux C., Schmitt-Verhulst A. M., Fitch F., Hood L., Malissen B. Direct evidence for chromosomal inversion during T-cell receptor beta-gene rearrangements. Nature. 1986 Jan 2;319(6048):28–33. doi: 10.1038/319028a0. [DOI] [PubMed] [Google Scholar]
- Malissen M., Trucy J., Letourneur F., Rebaï N., Dunn D. E., Fitch F. W., Hood L., Malissen B. A T cell clone expresses two T cell receptor alpha genes but uses one alpha beta heterodimer for allorecognition and self MHC-restricted antigen recognition. Cell. 1988 Oct 7;55(1):49–59. doi: 10.1016/0092-8674(88)90008-6. [DOI] [PubMed] [Google Scholar]
- Marolleau J. P., Fondell J. D., Malissen M., Trucy J., Barbier E., Marcu K. B., Cazenave P. A., Primi D. The joining of germ-line V alpha to J alpha genes replaces the preexisting V alpha-J alpha complexes in a T cell receptor alpha, beta positive T cell line. Cell. 1988 Oct 21;55(2):291–300. doi: 10.1016/0092-8674(88)90052-9. [DOI] [PubMed] [Google Scholar]
- McConnell T. J., Yokoyama W. M., Kikuchi G. E., Einhorn G. P., Stingl G., Shevach E. M., Coligan J. E. Delta-chains of dendritic epidermal T cell receptors are diverse but pair with gamma-chains in a restricted manner. J Immunol. 1989 Apr 15;142(8):2924–2931. [PubMed] [Google Scholar]
- Morgado M. G., Cam P., Gris-Liebe C., Cazenave P. A., Jouvin-Marche E. Further evidence that BALB/c and C57BL/6 gamma 2a genes originate from two distinct isotypes. EMBO J. 1989 Nov;8(11):3245–3251. doi: 10.1002/j.1460-2075.1989.tb08484.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Okazaki K., Sakano H. Thymocyte circular DNA excised from T cell receptor alpha-delta gene complex. EMBO J. 1988 Jun;7(6):1669–1674. doi: 10.1002/j.1460-2075.1988.tb02994.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Pech M., Jaenichen H. R., Pohlenz H. D., Neumaier P. S., Klobeck H. G., Zachau H. G. Organization and evolution of a gene cluster for human immunoglobulin variable regions of the kappa type. J Mol Biol. 1984 Jun 25;176(2):189–204. doi: 10.1016/0022-2836(84)90420-0. [DOI] [PubMed] [Google Scholar]
- Pech M., Smola H., Pohlenz H. D., Straubinger B., Gerl R., Zachau H. G. A large section of the gene locus encoding human immunoglobulin variable regions of the kappa type is duplicated. J Mol Biol. 1985 Jun 5;183(3):291–299. doi: 10.1016/0022-2836(85)90001-4. [DOI] [PubMed] [Google Scholar]
- Pircher H., Michalopoulos E. E., Iwamoto A., Ohashi P. S., Baenziger J., Hengartner H., Zinkernagel R. M., Mak T. W. Molecular analysis of the antigen receptor of virus-specific cytotoxic T cells and identification of a new V alpha family. Eur J Immunol. 1987 Dec;17(12):1843–1846. doi: 10.1002/eji.1830171226. [DOI] [PubMed] [Google Scholar]
- Primi D., Clynes R. A., Jouvin-Marche E., Marolleau J. P., Barbier E., Cazenave P. A., Marcu K. B. Rearrangement and expression of T cell receptor and immunoglobulin loci in immortalized CD4-CD8- T cell lines. Eur J Immunol. 1988 Jul;18(7):1101–1109. doi: 10.1002/eji.1830180720. [DOI] [PubMed] [Google Scholar]
- Rathbun G. A., Capra J. D., Tucker P. W. Organization of the murine immunoglobulin VH complex in the inbred strains. EMBO J. 1987 Oct;6(10):2931–2937. doi: 10.1002/j.1460-2075.1987.tb02597.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- Saito H., Kranz D. M., Takagaki Y., Hayday A. C., Eisen H. N., Tonegawa S. A third rearranged and expressed gene in a clone of cytotoxic T lymphocytes. Nature. 1984 Nov 1;312(5989):36–40. doi: 10.1038/312036a0. [DOI] [PubMed] [Google Scholar]
- Sherman D. H., Hochman P. S., Dick R., Tizard R., Ramachandran K. L., Flavell R. A., Huber B. T. Molecular analysis of antigen recognition by insulin-specific T-cell hybridomas from B6 wild-type and bm12 mutant mice. Mol Cell Biol. 1987 May;7(5):1865–1872. doi: 10.1128/mcb.7.5.1865. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Singer P. A., McEvilly R. J., Balderas R. S., Dixon F. J., Theofilopoulos A. N. T-cell receptor alpha-chain variable-region haplotypes of normal and autoimmune laboratory mouse strains. Proc Natl Acad Sci U S A. 1988 Oct;85(20):7729–7733. doi: 10.1073/pnas.85.20.7729. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Takagaki Y., Nakanishi N., Ishida I., Kanagawa O., Tonegawa S. T cell receptor-gamma and -delta genes preferentially utilized by adult thymocytes for the surface expression. J Immunol. 1989 Mar 15;142(6):2112–2121. [PubMed] [Google Scholar]
- Takeshita S., Toda M., Yamagishi H. Excision products of the T cell receptor gene support a progressive rearrangement model of the alpha/delta locus. EMBO J. 1989 Nov;8(11):3261–3270. doi: 10.1002/j.1460-2075.1989.tb08486.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Urban J. L., Kumar V., Kono D. H., Gomez C., Horvath S. J., Clayton J., Ando D. G., Sercarz E. E., Hood L. Restricted use of T cell receptor V genes in murine autoimmune encephalomyelitis raises possibilities for antibody therapy. Cell. 1988 Aug 12;54(4):577–592. doi: 10.1016/0092-8674(88)90079-7. [DOI] [PubMed] [Google Scholar]
- Winoto A., Baltimore D. Alpha beta lineage-specific expression of the alpha T cell receptor gene by nearby silencers. Cell. 1989 Nov 17;59(4):649–655. doi: 10.1016/0092-8674(89)90010-x. [DOI] [PubMed] [Google Scholar]
- Yague J., Blackman M., Born W., Marrack P., Kappler J., Palmer E. The structure of V alpha and J alpha segments in the mouse. Nucleic Acids Res. 1988 Dec 9;16(23):11355–11364. doi: 10.1093/nar/16.23.11355. [DOI] [PMC free article] [PubMed] [Google Scholar]