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. 1990 Aug;9(8):2485–2492. doi: 10.1002/j.1460-2075.1990.tb07427.x

A recombination event in the 5' flanking region of the Ly-6C gene correlates with impaired expression in the NOD, NZB and ST strains of mice.

W M Philbrick 1, S E Maher 1, M M Bridgett 1, A L Bothwell 1
PMCID: PMC552277  PMID: 2164472

Abstract

The murine alloantigen, Ly-6C, is found on 45% of bone marrow cells, 25% of splenocytes and 15% of lymph node cells in all inbred strains of mice tested, with the exception of NOD, NZB and ST. In these three strains, Ly-6C expression can be detected on only 5% of bone marrow cells and not at all on cells from spleen or lymph node. NOD and NZB, which are models for the autoimmune diseases, diabetes and lupus, respectively, also exhibit a depressed syngeneic mixed lymphocyte reaction. Southern blot analysis reveals a restriction fragment length polymorphism involving the Ly-6C gene which is unique to these three strains. Cloning of the affected genomic segment from the NOD mouse indicates the presence of an interruption in the flanking region of the Ly-6C gene at a point 475 bp upstream of the transcription initiation site and the consequent separation of distal 5' sequences from the body of the gene by at least 10 kb. Inspection of the recombination borders reveals a set of inverted copies of a mouse repetitive R element. Transfection of the Ly-6C genes from NOD and BALB/c into a murine carcinoma line indicates relative functional impairment of the NOD gene, thus paralleling performance in vivo.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Auchincloss H., Jr, Ozato K., Sachs D. H. Two distinct murine differentiation antigens determined by genes linked to the Ly-6 locus. J Immunol. 1981 Nov;127(5):1839–1843. [PubMed] [Google Scholar]
  2. Bertram J. S., Janik P. Establishment of a cloned line of Lewis Lung Carcinoma cells adapted to cell culture. Cancer Lett. 1980 Nov;11(1):63–73. doi: 10.1016/0304-3835(80)90130-5. [DOI] [PubMed] [Google Scholar]
  3. Bocchieri M. H., Cooke A., Smith J. B., Weigert M., Riblet R. J. Independent segregation of NZB immune abnormalities in NZB x C58 recombinant inbred mice. Eur J Immunol. 1982 Apr;12(4):349–354. doi: 10.1002/eji.1830120417. [DOI] [PubMed] [Google Scholar]
  4. Bocchieri M. H., Riblet R. J., Smith J. B. Autologous mixed lymphocyte reactions in NZB mice: analysis in recombinant inbred lines shows a T cell defect unrelated to autoantibody production. Eur J Immunol. 1981 Feb;11(2):159–162. doi: 10.1002/eji.1830110219. [DOI] [PubMed] [Google Scholar]
  5. Bothwell A., Pace P. E., LeClair K. P. Isolation and expression of an IFN-responsive Ly-6C chromosomal gene. J Immunol. 1988 Apr 15;140(8):2815–2820. [PubMed] [Google Scholar]
  6. Chandy K. G., Charles A. M., Kershnar A., Buckingham B., Waldeck N., Gupta S. Autologous mixed lymphocyte reaction in man: XV. Cellular and molecular basis of deficient autologous mixed lymphocyte response in insulin-dependent diabetes mellitus. J Clin Immunol. 1984 Nov;4(6):424–428. doi: 10.1007/BF00916571. [DOI] [PubMed] [Google Scholar]
  7. Davis L. S., Patel S. S., Atkinson J. P., Lipsky P. E. Decay-accelerating factor functions as a signal transducing molecule for human T cells. J Immunol. 1988 Oct 1;141(7):2246–2252. [PubMed] [Google Scholar]
  8. Dudley J. P. Discrete high molecular weight RNA transcribed from the long interspersed repetitive element L1Md. Nucleic Acids Res. 1987 Mar 25;15(6):2581–2592. doi: 10.1093/nar/15.6.2581. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Dumont F. J., Coker L. Z., Habbersett R. C., Treffinger J. A. Xenogeneic monoclonal antibody to an Ly-6-linked murine cell surface antigen: differential reactivity with T cell subpopulations and bone marrow cells. J Immunol. 1985 Apr;134(4):2357–2365. [PubMed] [Google Scholar]
  10. Dumont F. J., Coker L. Z. Interferon-alpha/beta enhances the expression of Ly-6 antigens on T cells in vivo and in vitro. Eur J Immunol. 1986 Jul;16(7):735–740. doi: 10.1002/eji.1830160704. [DOI] [PubMed] [Google Scholar]
  11. Dumont F. J., Dijkmans R., Palfree R. G., Boltz R. D., Coker L. Selective up-regulation by interferon-gamma of surface molecules of the Ly-6 complex in resting T cells: the Ly-6A/E and TAP antigens are preferentially enhanced. Eur J Immunol. 1987 Aug;17(8):1183–1191. doi: 10.1002/eji.1830170816. [DOI] [PubMed] [Google Scholar]
  12. 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]
  13. Glimcher L. H., Longo D. L., Green I., Schwartz R. H. Murine syngeneic mixed lymphocyte response. I. Target antigens are self Ia molecules. J Exp Med. 1981 Nov 1;154(5):1652–1670. doi: 10.1084/jem.154.5.1652. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Gunter K. C., Germain R. N., Kroczek R. A., Saito T., Yokoyama W. M., Chan C., Weiss A., Shevach E. M. Thy-1-mediated T-cell activation requires co-expression of CD3/Ti complex. Nature. 1987 Apr 2;326(6112):505–507. doi: 10.1038/326505a0. [DOI] [PubMed] [Google Scholar]
  15. Harada M., Makino S. Promotion of spontaneous diabetes in non-obese diabetes-prone mice by cyclophosphamide. Diabetologia. 1984 Dec;27(6):604–606. doi: 10.1007/BF00276978. [DOI] [PubMed] [Google Scholar]
  16. Havran W. L., Lancki D. W., Moldwin R. L., Dialynas D. P., Fitch F. W. Characterization of an anti-Ly-6 monoclonal antibody which defines and activates cytolytic T lymphocytes. J Immunol. 1988 Feb 15;140(4):1034–1042. [PubMed] [Google Scholar]
  17. Holguin M. H., Fredrick L. R., Bernshaw N. J., Wilcox L. A., Parker C. J. Isolation and characterization of a membrane protein from normal human erythrocytes that inhibits reactive lysis of the erythrocytes of paroxysmal nocturnal hemoglobinuria. J Clin Invest. 1989 Jul;84(1):7–17. doi: 10.1172/JCI114172. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Jubier-Maurin V., Dod B. J., Bellis M., Piechaczyk M., Roizes G. Comparative study of the L1 family in the genus Mus. Possible role of retroposition and conversion events in its concerted evolution. J Mol Biol. 1985 Aug 20;184(4):547–564. doi: 10.1016/0022-2836(85)90302-x. [DOI] [PubMed] [Google Scholar]
  19. Jutila M. A., Kroese F. G., Jutila K. L., Stall A. M., Fiering S., Herzenberg L. A., Berg E. L., Butcher E. C. Ly-6C is a monocyte/macrophage and endothelial cell differentiation antigen regulated by interferon-gamma. Eur J Immunol. 1988 Nov;18(11):1819–1826. doi: 10.1002/eji.1830181125. [DOI] [PubMed] [Google Scholar]
  20. Kelley V. E., Winkelstein A. Age- and sex-related glomerulonephritis in New Zealand white mice. Clin Immunol Immunopathol. 1980 Jun;16(2):142–150. doi: 10.1016/0090-1229(80)90198-1. [DOI] [PubMed] [Google Scholar]
  21. Kimura S., Tada N., Liu-Lam Y., Hämmerling U. Studies of the mouse Ly-6 alloantigen system. II. Complexities of the Ly-6 region. Immunogenetics. 1984;20(1):47–56. doi: 10.1007/BF00373446. [DOI] [PubMed] [Google Scholar]
  22. LeClair K. P., Bridgett M. M., Dumont F. J., Palfree R. G., Hämmerling U., Bothwell A. L. Kinetic analysis of Ly-6 gene induction in a T lymphoma by interferons and interleukin 1, and demonstration of Ly-6 inducibility in diverse cell types. Eur J Immunol. 1989 Jul;19(7):1233–1239. doi: 10.1002/eji.1830190713. [DOI] [PubMed] [Google Scholar]
  23. LeClair K. P., Palfree R. G., Flood P. M., Hammerling U., Bothwell A. Isolation of a murine Ly-6 cDNA reveals a new multigene family. EMBO J. 1986 Dec 1;5(12):3227–3234. doi: 10.1002/j.1460-2075.1986.tb04633.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. LeClair K. P., Rabin M., Nesbitt M. N., Pravtcheva D., Ruddle F. H., Palfree R. G., Bothwell A. Murine Ly-6 multigene family is located on chromosome 15. Proc Natl Acad Sci U S A. 1987 Mar;84(6):1638–1642. doi: 10.1073/pnas.84.6.1638. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Leiter E. H., Prochazka M., Coleman D. L. The non-obese diabetic (NOD) mouse. Am J Pathol. 1987 Aug;128(2):380–383. [PMC free article] [PubMed] [Google Scholar]
  26. Leo O., Foo M., Forman J., Shivakumar S., Rabinowitz R., Bluestone J. A. Selective expression of the Ly-6C.2 epitope on Lyt-2+ T cells that can develop in the absence of thymic influence. J Immunol. 1988 Jul 1;141(1):37–44. [PubMed] [Google Scholar]
  27. Loeb D. D., Padgett R. W., Hardies S. C., Shehee W. R., Comer M. B., Edgell M. H., Hutchison C. A., 3rd The sequence of a large L1Md element reveals a tandemly repeated 5' end and several features found in retrotransposons. Mol Cell Biol. 1986 Jan;6(1):168–182. doi: 10.1128/mcb.6.1.168. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Low M. G., Kincade P. W. Phosphatidylinositol is the membrane-anchoring domain of the Thy-1 glycoprotein. Nature. 1985 Nov 7;318(6041):62–64. doi: 10.1038/318062a0. [DOI] [PubMed] [Google Scholar]
  29. Makino S., Kunimoto K., Muraoka Y., Katagiri K. Effect of castration on the appearance of diabetes in NOD mouse. Jikken Dobutsu. 1981 Apr;30(2):137–140. doi: 10.1538/expanim1978.30.2_137. [DOI] [PubMed] [Google Scholar]
  30. Makino S., Kunimoto K., Muraoka Y., Mizushima Y., Katagiri K., Tochino Y. Breeding of a non-obese, diabetic strain of mice. Jikken Dobutsu. 1980 Jan;29(1):1–13. doi: 10.1538/expanim1978.29.1_1. [DOI] [PubMed] [Google Scholar]
  31. Miura O., Sugahara Y., Nakamura Y., Hirosawa S., Aoki N. Restriction fragment length polymorphism caused by a deletion involving Alu sequences within the human alpha 2-plasmin inhibitor gene. Biochemistry. 1989 Jun 13;28(12):4934–4938. doi: 10.1021/bi00438a003. [DOI] [PubMed] [Google Scholar]
  32. Murray N. E., Brammar W. J., Murray K. Lambdoid phages that simplify the recovery of in vitro recombinants. Mol Gen Genet. 1977 Jan 7;150(1):53–61. doi: 10.1007/BF02425325. [DOI] [PubMed] [Google Scholar]
  33. Palfree R. G., LeClair K. P., Bothwell A., Hämmerling U. cDNA characterization of an Ly-6.2 gene expressed in BW5147 tumor cells. Immunogenetics. 1987;26(6):389–391. doi: 10.1007/BF00343712. [DOI] [PubMed] [Google Scholar]
  34. Palfree R. G., Sirlin S., Dumont F. J., Hämmerling U. N-terminal and cDNA characterization of murine lymphocyte antigen Ly-6C.2. J Immunol. 1988 Jan 1;140(1):305–310. [PubMed] [Google Scholar]
  35. Philbrick W. M., Palfree R. G., Maher S. E., Bridgett M. M., Sirlin S., Bothwell A. L. The CD59 antigen is a structural homologue of murine Ly-6 antigens but lacks interferon inducibility. Eur J Immunol. 1990 Jan;20(1):87–92. doi: 10.1002/eji.1830200113. [DOI] [PubMed] [Google Scholar]
  36. Reich E. P., Scaringe D., Yagi J., Sherwin R. S., Janeway C. A., Jr Prevention of diabetes in NOD mice by injection of autoreactive T-lymphocytes. Diabetes. 1989 Dec;38(12):1647–1651. doi: 10.2337/diab.38.12.1647. [DOI] [PubMed] [Google Scholar]
  37. Rock K. L., Reiser H., Bamezai A., McGrew J., Benacerraf B. The LY-6 locus: a multigene family encoding phosphatidylinositol-anchored membrane proteins concerned with T-cell activation. Immunol Rev. 1989 Oct;111:195–224. doi: 10.1111/j.1600-065x.1989.tb00547.x. [DOI] [PubMed] [Google Scholar]
  38. Saffer J. D., Thurston S. J. A negative regulatory element with properties similar to those of enhancers is contained within an Alu sequence. Mol Cell Biol. 1989 Feb;9(2):355–364. doi: 10.1128/mcb.9.2.355. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Schmid I., Schmid P., Giorgi J. V. Conversion of logarithmic channel numbers into relative linear fluorescence intensity. Cytometry. 1988 Nov;9(6):533–538. doi: 10.1002/cyto.990090605. [DOI] [PubMed] [Google Scholar]
  40. Serreze D. V., Leiter E. H. Defective activation of T suppressor cell function in nonobese diabetic mice. Potential relation to cytokine deficiencies. J Immunol. 1988 Jun 1;140(11):3801–3807. [PubMed] [Google Scholar]
  41. Shevach E. M., Korty P. E. Ly-6: a multigene family in search of a function. Immunol Today. 1989 Jun;10(6):195–200. doi: 10.1016/0167-5699(89)90324-1. [DOI] [PubMed] [Google Scholar]
  42. Smith J. B., Pasternak R. D. Syngeneic mixed lymphocyte reaction in mice: strain distribution, kinetics, participating cells, and absence in NZB mice. J Immunol. 1978 Nov;121(5):1889–1892. [PubMed] [Google Scholar]
  43. Southern P. J., Berg P. Transformation of mammalian cells to antibiotic resistance with a bacterial gene under control of the SV40 early region promoter. J Mol Appl Genet. 1982;1(4):327–341. [PubMed] [Google Scholar]
  44. Steinberg A. D., Huston D. P., Taurog J. D., Cowdery J. S., Ravecheé E. S. The cellular and genetic basis of murine lupus. Immunol Rev. 1981;55:121–154. doi: 10.1111/j.1600-065x.1981.tb00341.x. [DOI] [PubMed] [Google Scholar]
  45. Su B., Bothwell A. L. Biosynthesis of a phosphatidylinositol-glycan-linked membrane protein: signals for posttranslational processing of the Ly-6E antigen. Mol Cell Biol. 1989 Aug;9(8):3369–3376. doi: 10.1128/mcb.9.8.3369. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Swain S. L. T cell subsets and the recognition of MHC class. Immunol Rev. 1983;74:129–142. doi: 10.1111/j.1600-065x.1983.tb01087.x. [DOI] [PubMed] [Google Scholar]
  47. Tolberg M. E., Funderburk S. J., Klisak I., Smith S. S. Structural organization and DNA methylation patterning within the mouse L1 family. J Biol Chem. 1987 Aug 15;262(23):11167–11175. [PubMed] [Google Scholar]
  48. Voliva C. F., Martin S. L., Hutchison C. A., 3rd, Edgell M. H. Dispersal process associated with the L1 family of interspersed repetitive DNA sequences. J Mol Biol. 1984 Oct 5;178(4):795–813. doi: 10.1016/0022-2836(84)90312-7. [DOI] [PubMed] [Google Scholar]
  49. Volk H. D., Diamantstein T. IL-2 normalizes defective suppressor T cell function of patients with systemic lupus erythematosus in vitro. Clin Exp Immunol. 1986 Dec;66(3):525–531. [PMC free article] [PubMed] [Google Scholar]
  50. Waneck G. L., Stein M. E., Flavell R. A. Conversion of a PI-anchored protein to an integral membrane protein by a single amino acid mutation. Science. 1988 Aug 5;241(4866):697–699. doi: 10.1126/science.3399901. [DOI] [PubMed] [Google Scholar]
  51. Weber T., Schmitt H. P., Alonso A. Differential transcription of the repetitive R-element in various mouse cell types. Gene. 1987;53(1):105–111. doi: 10.1016/0378-1119(87)90097-7. [DOI] [PubMed] [Google Scholar]
  52. Whittaker P. A., Campbell A. J., Southern E. M., Murray N. E. Enhanced recovery and restriction mapping of DNA fragments cloned in a new lambda vector. Nucleic Acids Res. 1988 Jul 25;16(14B):6725–6736. doi: 10.1093/nar/16.14.6725. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Wicker L. S., Miller B. J., Coker L. Z., McNally S. E., Scott S., Mullen Y., Appel M. C. Genetic control of diabetes and insulitis in the nonobese diabetic (NOD) mouse. J Exp Med. 1987 Jun 1;165(6):1639–1654. doi: 10.1084/jem.165.6.1639. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Williams A. F., Tse A. G., Gagnon J. Squid glycoproteins with structural similarities to Thy-1 and Ly-6 antigens. Immunogenetics. 1988;27(4):265–272. doi: 10.1007/BF00376121. [DOI] [PubMed] [Google Scholar]
  55. Yamashita U., Ono S., Nakamura H. The syngeneic mixed leukocyte reaction in mice. II. The I region control of suppressor T cell activity induced in the syngeneic mixed leukocyte reaction. J Immunol. 1982 Mar;128(3):1010–1017. [PubMed] [Google Scholar]
  56. Yeh E. T., Reiser H., Bamezai A., Rock K. L. TAP transcription and phosphatidylinositol linkage mutants are defective in activation through the T cell receptor. Cell. 1988 Mar 11;52(5):665–674. doi: 10.1016/0092-8674(88)90404-7. [DOI] [PubMed] [Google Scholar]

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