Abstract
During derivation of transgenic mouse strains with various TL and TL/H- 2 chimeric genes, one strain, Tg.Tlaa-3-1, introduced with a TL gene (Tlaa-3), was found to have an abnormal thymic T cell population and to develop a high incidence of T cell lymphomas. To investigate the etiology of the thymic abnormalities and of the lymphomas, the development of lymphoid organs in transgenic mice was studied. The thymus of these mice goes through three unusual successive events: perturbation of thymic development during embryogenesis, disappearance of thymocytes between day 14 and day 21 after birth, and subsequent proliferation of large blast-like cells. These events are associated with the abolishment of T cell receptor (TCR) alpha beta lineage of the T cell differentiation, leading to preponderance of cells belonging to the TCR gamma delta L3T4-Lyt-2- double negative (DN) lineage. Bone marrow transplantation and thymic graft experiments demonstrate that the abnormality resides in the bone marrow stem cells rather than in the thymic environment. The expression of TL antigen in the transgenic mice is greatly increased and TL is expressed in a wide range of T cells, including normally TL- DN cells and L3T4+ Lyt-2- and L3T4-Lyt-2+ single positive cells. These quantitative and qualitative abnormalities in TL expression most likely cause the abnormal T cell differentiation. The gamma delta DN cells migrate into peripheral lymphoid organs and constitute nearly 50% of peripheral T cells. Immune function of the transgenic mice is severely impaired, as T cell function is defective in antibody production to sheep red blood cells, in mixed lymphocyte culture reaction to allogenic spleen cells and also in stimulation with concanavalin A. These results indicate that the gamma delta cells are incapable of participating in these reactions. Molecular and serological analysis of T cell lymphomas reveal that they belong to the gamma delta lineage, suggesting that the gamma delta DN cells in this strain are susceptible to leukemic transformation. Based on cell surface phenotype and TCR expression of the DN thymocytes and T cell lymphomas, a map of the sequential steps involved in the differentiation of gamma delta DN cells is proposed.(ABSTRACT TRUNCATED AT 400 WORDS)
Full Text
The Full Text of this article is available as a PDF (1.9 MB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Adams J. M., Harris A. W., Pinkert C. A., Corcoran L. M., Alexander W. S., Cory S., Palmiter R. D., Brinster R. L. The c-myc oncogene driven by immunoglobulin enhancers induces lymphoid malignancy in transgenic mice. Nature. 1985 Dec 12;318(6046):533–538. doi: 10.1038/318533a0. [DOI] [PubMed] [Google Scholar]
- Blackman M., Kappler J., Marrack P. The role of the T cell receptor in positive and negative selection of developing T cells. Science. 1990 Jun 15;248(4961):1335–1341. doi: 10.1126/science.1972592. [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]
- Brenner M. B., McLean J., Dialynas D. P., Strominger J. L., Smith J. A., Owen F. L., Seidman J. G., Ip S., Rosen F., Krangel M. S. Identification of a putative second T-cell receptor. Nature. 1986 Jul 10;322(6075):145–149. doi: 10.1038/322145a0. [DOI] [PubMed] [Google Scholar]
- Bruce J., Symington F. W., McKearn T. J., Sprent J. A monoclonal antibody discriminating between subsets of T and B cells. J Immunol. 1981 Dec;127(6):2496–2501. [PubMed] [Google Scholar]
- Chen Y. T., Obata Y., Stockert E., Old L. J. Thymus-leukemia (TL) antigens of the mouse. Analysis of TL mRNA and TL cDNA TL+ and TL- strains. J Exp Med. 1985 Oct 1;162(4):1134–1148. doi: 10.1084/jem.162.4.1134. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- DUNN T. B. Normal and pathologic anatomy of the reticular tissue in laboratory mice, with a classification and discussion of neoplasms. J Natl Cancer Inst. 1954 Jun;14(6):1281–1433. [PubMed] [Google Scholar]
- Dialynas D. P., Quan Z. S., Wall K. A., Pierres A., Quintáns J., Loken M. R., Pierres M., Fitch F. W. Characterization of the murine T cell surface molecule, designated L3T4, identified by monoclonal antibody GK1.5: similarity of L3T4 to the human Leu-3/T4 molecule. J Immunol. 1983 Nov;131(5):2445–2451. [PubMed] [Google Scholar]
- Fisher D. A., Hunt S. W., 3rd, Hood L. Structure of a gene encoding a murine thymus leukemia antigen, and organization of Tla genes in the BALB/c mouse. J Exp Med. 1985 Aug 1;162(2):528–545. doi: 10.1084/jem.162.2.528. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Fowlkes B. J., Pardoll D. M. Molecular and cellular events of T cell development. Adv Immunol. 1989;44:207–264. doi: 10.1016/s0065-2776(08)60643-4. [DOI] [PubMed] [Google Scholar]
- Gordon J. W., Scangos G. A., Plotkin D. J., Barbosa J. A., Ruddle F. H. Genetic transformation of mouse embryos by microinjection of purified DNA. Proc Natl Acad Sci U S A. 1980 Dec;77(12):7380–7384. doi: 10.1073/pnas.77.12.7380. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hershberg R., Eghtesady P., Sydora B., Brorson K., Cheroutre H., Modlin R., Kronenberg M. Expression of the thymus leukemia antigen in mouse intestinal epithelium. Proc Natl Acad Sci U S A. 1990 Dec;87(24):9727–9731. doi: 10.1073/pnas.87.24.9727. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ito K., Van Kaer L., Bonneville M., Hsu S., Murphy D. B., Tonegawa S. Recognition of the product of a novel MHC TL region gene (27b) by a mouse gamma delta T cell receptor. Cell. 1990 Aug 10;62(3):549–561. doi: 10.1016/0092-8674(90)90019-b. [DOI] [PubMed] [Google Scholar]
- 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]
- Iwamoto A., Rupp F., Ohashi P. S., Walker C. L., Pircher H., Joho R., Hengartner H., Mak T. W. T cell-specific gamma genes in C57BL/10 mice. Sequence and expression of new constant and variable region genes. J Exp Med. 1986 May 1;163(5):1203–1212. doi: 10.1084/jem.163.5.1203. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kay M. M. Immunologic aging patterns: effect of parainfluenza type 1 virus infection on aging mice of eight strains and hybrids. Birth Defects Orig Artic Ser. 1978;14(1):213–240. [PubMed] [Google Scholar]
- Kishihara K., Yoshikai Y., Matsuzaki G., Tomooka S., Nomoto K. "Radioresistant" intrathymic T cell precursors express T cell receptor C gamma 4- and C delta-specific gene messages. Eur J Immunol. 1988 Jun;18(6):841–847. doi: 10.1002/eji.1830180603. [DOI] [PubMed] [Google Scholar]
- Kubo R. T., Born W., Kappler J. W., Marrack P., Pigeon M. Characterization of a monoclonal antibody which detects all murine alpha beta T cell receptors. J Immunol. 1989 Apr 15;142(8):2736–2742. [PubMed] [Google Scholar]
- Ledbetter J. A., Herzenberg L. A. Xenogeneic monoclonal antibodies to mouse lymphoid differentiation antigens. Immunol Rev. 1979;47:63–90. doi: 10.1111/j.1600-065x.1979.tb00289.x. [DOI] [PubMed] [Google Scholar]
- Leo O., Foo M., Sachs D. H., Samelson L. E., Bluestone J. A. Identification of a monoclonal antibody specific for a murine T3 polypeptide. Proc Natl Acad Sci U S A. 1987 Mar;84(5):1374–1378. doi: 10.1073/pnas.84.5.1374. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Malek T. R., Robb R. J., Shevach E. M. Identification and initial characterization of a rat monoclonal antibody reactive with the murine interleukin 2 receptor-ligand complex. Proc Natl Acad Sci U S A. 1983 Sep;80(18):5694–5698. doi: 10.1073/pnas.80.18.5694. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Maxam A. M., Gilbert W. Sequencing end-labeled DNA with base-specific chemical cleavages. Methods Enzymol. 1980;65(1):499–560. doi: 10.1016/s0076-6879(80)65059-9. [DOI] [PubMed] [Google Scholar]
- Muto M., Kubo E., Kamisaku H., Sado T. Phenotypic characterization of thymic prelymphoma cells of B10 mice treated with split-dose irradiation. J Immunol. 1990 Feb 1;144(3):849–853. [PubMed] [Google Scholar]
- Müller E., Müntener M. Short time observations of morphological changes and cholinesterase distribution in lymphatic organs of the mouse after corticosteroid and X-ray treatment. Histochemistry. 1979 Apr 3;60(2):169–180. doi: 10.1007/BF00495752. [DOI] [PubMed] [Google Scholar]
- OLD L. J., BOYSE E. A. ANTIGENIC PROPERTIES OF EXPERIMENTAL LEUKEMIAS. I. SEROLOGICAL STUDIES IN VITRO WITH SPONTANEOUS AND RADIATION-INDUCED LEUKEMIAS. J Natl Cancer Inst. 1963 Oct;31:977–995. [PubMed] [Google Scholar]
- Obata Y., Chen Y. T., Stockert E., Old L. J. Structural analysis of TL genes of the mouse. Proc Natl Acad Sci U S A. 1985 Aug;82(16):5475–5479. doi: 10.1073/pnas.82.16.5475. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Obata Y., Stockert E., Chen Y. T., Takahashi T., Old L. J. Influence of 5' flanking sequences on TL and H-2 expression in transfected L cells. Proc Natl Acad Sci U S A. 1988 May;85(10):3541–3545. doi: 10.1073/pnas.85.10.3541. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Picker L. J., Brenner M. B., Michie S., Warnke R. A. Expression of T cell receptor delta chains in benign and malignant T lineage lymphoproliferations. Am J Pathol. 1988 Sep;132(3):401–405. [PMC free article] [PubMed] [Google Scholar]
- Pontarotti P. A., Mashimo H., Zeff R. A., Fisher D. A., Hood L., Mellor A., Flavell R. A., Nathenson S. G. Conservation and diversity in the class I genes of the major histocompatibility complex: sequence analysis of a Tlab gene and comparison with a Tlac gene. Proc Natl Acad Sci U S A. 1986 Mar;83(6):1782–1786. doi: 10.1073/pnas.83.6.1782. [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]
- Rigby P. W., Dieckmann M., Rhodes C., Berg P. Labeling deoxyribonucleic acid to high specific activity in vitro by nick translation with DNA polymerase I. J Mol Biol. 1977 Jun 15;113(1):237–251. doi: 10.1016/0022-2836(77)90052-3. [DOI] [PubMed] [Google Scholar]
- Sha W. C., Nelson C. A., Newberry R. D., Pullen J. K., Pease L. R., Russell J. H., Loh D. Y. Positive selection of transgenic receptor-bearing thymocytes by Kb antigen is altered by Kb mutations that involve peptide binding. Proc Natl Acad Sci U S A. 1990 Aug;87(16):6186–6190. doi: 10.1073/pnas.87.16.6186. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Smith G. S., Walford R. L. Influence of the H-2 and H-1 histocompatibility systems upon life span and spontaneous cancer incidences in congenic mice. Birth Defects Orig Artic Ser. 1978;14(1):281–312. [PubMed] [Google Scholar]
- Southern E. M. Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Mol Biol. 1975 Nov 5;98(3):503–517. doi: 10.1016/s0022-2836(75)80083-0. [DOI] [PubMed] [Google Scholar]
- Stockert E., Old L. J. Preleukemic expression of TL antigens in x-irradiated C57BL/6 mice. J Exp Med. 1977 Jul 1;146(1):271–276. doi: 10.1084/jem.146.1.271. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Strominger J. L. The gamma delta T cell receptor and class Ib MHC-related proteins: enigmatic molecules of immune recognition. Cell. 1989 Jun 16;57(6):895–898. doi: 10.1016/0092-8674(89)90326-7. [DOI] [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]
- Thomas P. S. Hybridization of denatured RNA and small DNA fragments transferred to nitrocellulose. Proc Natl Acad Sci U S A. 1980 Sep;77(9):5201–5205. doi: 10.1073/pnas.77.9.5201. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tkachuk D. C., Griesser H., Takihara Y., Champagne E., Minden M., Feller A. C., Lennert K., Mak T. W. Rearrangement of T-cell delta locus in lymphoproliferative disorders. Blood. 1988 Jul;72(1):353–357. [PubMed] [Google Scholar]
- Van Kaer L., Wu M., Ichikawa Y., Ito K., Bonneville M., Ostrand-Rosenberg S., Murphy D. B., Tonegawa S. Recognition of MHC TL gene products by gamma delta T cells. Immunol Rev. 1991 Apr;120:89–115. doi: 10.1111/j.1600-065x.1991.tb00589.x. [DOI] [PubMed] [Google Scholar]
- Yukawa K., Kikutani H., Inomoto T., Uehira M., Bin S. H., Akagi K., Yamamura K., Kishimoto T. Strain dependency of B and T lymphoma development in immunoglobulin heavy chain enhancer (E mu)-myc transgenic mice. J Exp Med. 1989 Sep 1;170(3):711–726. doi: 10.1084/jem.170.3.711. [DOI] [PMC free article] [PubMed] [Google Scholar]