Abstract
The effect of thymic selection on the expressed human T-cell antigen receptor beta-chain variable region (V beta) gene repertoire was examined by using a multiprobe RNase protection assay. The relative abundance of transcripts for 22 V beta genes (encompassing 17 of the 20 human V beta gene subfamilies) within a thymus, and among 17 thymuses, was variable. On the basis of the presence of corresponding mRNAs, no genomic deletions were detected, but several coding region polymorphisms were identified. Analysis of mature T-cell subsets revealed the absence of complete "superantigen"-mediated V beta deletions, suggesting that this phenomenon, in contrast to mouse, is uncommon or absent in humans. However, several V beta genes were over- or underexpressed in one or both mature single-positive (CD4+8- or CD8+4-) thymocyte subsets compared to syngeneic total, mostly immature thymocytes. Whether these changes are induced by relatively weak superantigens or conventional antigens and whether the downshifts are caused by negative selection or lack of positive selection remains to be determined.
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- Behlke M. A., Chou H. S., Huppi K., Loh D. Y. Murine T-cell receptor mutants with deletions of beta-chain variable region genes. Proc Natl Acad Sci U S A. 1986 Feb;83(3):767–771. doi: 10.1073/pnas.83.3.767. [DOI] [PMC free article] [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]
- Choi Y. W., Kotzin B., Herron L., Callahan J., Marrack P., Kappler J. Interaction of Staphylococcus aureus toxin "superantigens" with human T cells. Proc Natl Acad Sci U S A. 1989 Nov;86(22):8941–8945. doi: 10.1073/pnas.86.22.8941. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
- Concannon P., Gatti R. A., Hood L. E. Human T cell receptor V beta gene polymorphism. J Exp Med. 1987 Apr 1;165(4):1130–1140. doi: 10.1084/jem.165.4.1130. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Concannon P., Pickering L. A., Kung P., Hood L. Diversity and structure of human T-cell receptor beta-chain variable region genes. Proc Natl Acad Sci U S A. 1986 Sep;83(17):6598–6602. doi: 10.1073/pnas.83.17.6598. [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]
- Duby A. D., Seidman J. G. Abnormal recombination products result from aberrant DNA rearrangement of the human T-cell antigen receptor beta-chain gene. Proc Natl Acad Sci U S A. 1986 Jul;83(13):4890–4894. doi: 10.1073/pnas.83.13.4890. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Dyson P. J., Knight A. M., Fairchild S., Simpson E., Tomonari K. Genes encoding ligands for deletion of V beta 11 T cells cosegregate with mammary tumour virus genomes. Nature. 1991 Feb 7;349(6309):531–532. doi: 10.1038/349531a0. [DOI] [PubMed] [Google Scholar]
- Fink P. J., Matis L. A., McElligott D. L., Bookman M., Hedrick S. M. Correlations between T-cell specificity and the structure of the antigen receptor. Nature. 1986 May 15;321(6067):219–226. doi: 10.1038/321219a0. [DOI] [PubMed] [Google Scholar]
- Frankel W. N., Rudy C., Coffin J. M., Huber B. T. Linkage of Mls genes to endogenous mammary tumour viruses of inbred mice. Nature. 1991 Feb 7;349(6309):526–528. doi: 10.1038/349526a0. [DOI] [PubMed] [Google Scholar]
- Haqqi T. M., Banerjee S., Anderson G. D., David C. S. RIII S/J (H-2r). An inbred mouse strain with a massive deletion of T cell receptor V beta genes. J Exp Med. 1989 Jun 1;169(6):1903–1909. doi: 10.1084/jem.169.6.1903. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Haqqi T. M., Banerjee S., Jones W. L., Anderson G., Behlke M. A., Loh D. Y., Luthra H. S., David C. S. Identification of T-cell receptor V beta deletion mutant mouse strain AU/ssJ (H-2q) which is resistant to collagen-induced arthritis. Immunogenetics. 1989;29(3):180–185. doi: 10.1007/BF00373643. [DOI] [PubMed] [Google Scholar]
- Huppi K. E., D'Hoostelaere L. A., Mock B. A., Jouvin-Marche E., Behlke M. A., Chou H. S., Berry R. J., Loh D. Y. T-cell receptor VT beta genes in natural populations of mice. Immunogenetics. 1988;27(1):51–56. doi: 10.1007/BF00404444. [DOI] [PubMed] [Google Scholar]
- Ikuta K., Ogura T., Shimizu A., Honjo T. Low frequency of somatic mutation in beta-chain variable region genes of human T-cell receptors. Proc Natl Acad Sci U S A. 1985 Nov;82(22):7701–7705. doi: 10.1073/pnas.82.22.7701. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jouvin-Marche E., Trede N. S., Bandeira A., Tomas A., Loh D. Y., Cazenave P. A. Different large deletions of T cell receptor V beta genes in natural populations of mice. Eur J Immunol. 1989 Oct;19(10):1921–1926. doi: 10.1002/eji.1830191024. [DOI] [PubMed] [Google Scholar]
- Kappler J. W., Roehm N., Marrack P. T cell tolerance by clonal elimination in the thymus. Cell. 1987 Apr 24;49(2):273–280. doi: 10.1016/0092-8674(87)90568-x. [DOI] [PubMed] [Google Scholar]
- Kappler J. W., Staerz U., White J., Marrack P. C. Self-tolerance eliminates T cells specific for Mls-modified products of the major histocompatibility complex. Nature. 1988 Mar 3;332(6159):35–40. doi: 10.1038/332035a0. [DOI] [PubMed] [Google Scholar]
- Kimura N., Toyonaga B., Yoshikai Y., Du R. P., Mak T. W. Sequences and repertoire of the human T cell receptor alpha and beta chain variable region genes in thymocytes. Eur J Immunol. 1987 Mar;17(3):375–383. doi: 10.1002/eji.1830170312. [DOI] [PubMed] [Google Scholar]
- Kimura N., Toyonaga B., Yoshikai Y., Triebel F., Debre P., Minden M. D., Mak T. W. Sequences and diversity of human T cell receptor beta chain variable region genes. J Exp Med. 1986 Sep 1;164(3):739–750. doi: 10.1084/jem.164.3.739. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lai E., Concannon P., Hood L. Conserved organization of the human and murine T-cell receptor beta-gene families. Nature. 1988 Feb 11;331(6156):543–546. doi: 10.1038/331543a0. [DOI] [PubMed] [Google Scholar]
- Leiden J. M., Strominger J. L. Generation of diversity of the beta chain of the human T-lymphocyte receptor for antigen. Proc Natl Acad Sci U S A. 1986 Jun;83(12):4456–4460. doi: 10.1073/pnas.83.12.4456. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Li Y., Szabo P., Robinson M. A., Dong B., Posnett D. N. Allelic variations in the human T cell receptor V beta 6.7 gene products. J Exp Med. 1990 Jan 1;171(1):221–230. doi: 10.1084/jem.171.1.221. [DOI] [PMC free article] [PubMed] [Google Scholar]
- MacDonald H. R., Schneider R., Lees R. K., Howe R. C., Acha-Orbea H., Festenstein H., Zinkernagel R. M., Hengartner H. T-cell receptor V beta use predicts reactivity and tolerance to Mlsa-encoded antigens. Nature. 1988 Mar 3;332(6159):40–45. doi: 10.1038/332040a0. [DOI] [PubMed] [Google Scholar]
- Marrack P., Kappler J. The staphylococcal enterotoxins and their relatives. Science. 1990 May 11;248(4956):705–711. doi: 10.1126/science.2185544. [DOI] [PubMed] [Google Scholar]
- Marrack P., Kushnir E., Kappler J. A maternally inherited superantigen encoded by a mammary tumour virus. Nature. 1991 Feb 7;349(6309):524–526. doi: 10.1038/349524a0. [DOI] [PubMed] [Google Scholar]
- Okada C. Y., Weissman I. L. Relative V beta transcript levels in thymus and peripheral lymphoid tissues from various mouse strains. Inverse correlation of I-E and Mls expression with relative abundance of several V beta transcripts in peripheral lymphoid tissues. J Exp Med. 1989 May 1;169(5):1703–1719. doi: 10.1084/jem.169.5.1703. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Pullen A. M., Marrack P., Kappler J. W. The T-cell repertoire is heavily influenced by tolerance to polymorphic self-antigens. Nature. 1988 Oct 27;335(6193):796–801. doi: 10.1038/335796a0. [DOI] [PubMed] [Google Scholar]
- Pullen A. M., Potts W., Wakeland E. K., Kappler J., Marrack P. Surprisingly uneven distribution of the T cell receptor V beta repertoire in wild mice. J Exp Med. 1990 Jan 1;171(1):49–62. doi: 10.1084/jem.171.1.49. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Robinson M. A. Allelic sequence variations in the hypervariable region of a T-cell receptor beta chain: correlation with restriction fragment length polymorphism in human families and populations. Proc Natl Acad Sci U S A. 1989 Dec;86(23):9422–9426. doi: 10.1073/pnas.86.23.9422. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Saiki R. K., Scharf S., Faloona F., Mullis K. B., Horn G. T., Erlich H. A., Arnheim N. Enzymatic amplification of beta-globin genomic sequences and restriction site analysis for diagnosis of sickle cell anemia. Science. 1985 Dec 20;230(4732):1350–1354. doi: 10.1126/science.2999980. [DOI] [PubMed] [Google Scholar]
- Sanger F., Nicklen S., Coulson A. R. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. doi: 10.1073/pnas.74.12.5463. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- Singer P. A., Balderas R. S., McEvilly R. J., Bobardt M., Theofilopoulos A. N. Tolerance-related V beta clonal deletions in normal CD4-8-, TCR-alpha/beta + and abnormal lpr and gld cell populations. J Exp Med. 1989 Dec 1;170(6):1869–1877. doi: 10.1084/jem.170.6.1869. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Singer P. A., Balderas R. S., Theofilopoulos A. N. Thymic selection defines multiple T cell receptor V beta 'repertoire phenotypes' at the CD4/CD8 subset level. EMBO J. 1990 Nov;9(11):3641–3648. doi: 10.1002/j.1460-2075.1990.tb07575.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tillinghast J. P., Behlke M. A., Loh D. Y. Structure and diversity of the human T-cell receptor beta-chain variable region genes. Science. 1986 Aug 22;233(4766):879–883. doi: 10.1126/science.3755549. [DOI] [PubMed] [Google Scholar]
- Toyonaga B., Mak T. W. Genes of the T-cell antigen receptor in normal and malignant T cells. Annu Rev Immunol. 1987;5:585–620. doi: 10.1146/annurev.iy.05.040187.003101. [DOI] [PubMed] [Google Scholar]
- Toyonaga B., Yoshikai Y., Vadasz V., Chin B., Mak T. W. Organization and sequences of the diversity, joining, and constant region genes of the human T-cell receptor beta chain. Proc Natl Acad Sci U S A. 1985 Dec;82(24):8624–8628. doi: 10.1073/pnas.82.24.8624. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tunnacliffe A., Kefford R., Milstein C., Forster A., Rabbitts T. H. Sequence and evolution of the human T-cell antigen receptor beta-chain genes. Proc Natl Acad Sci U S A. 1985 Aug;82(15):5068–5072. doi: 10.1073/pnas.82.15.5068. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Vacchio M. S., Hodes R. J. Selective decreases in T cell receptor V beta expression. Decreased expression of specific V beta families is associated with expression of multiple MHC and non-MHC gene products. J Exp Med. 1989 Oct 1;170(4):1335–1346. doi: 10.1084/jem.170.4.1335. [DOI] [PMC free article] [PubMed] [Google Scholar]
- White J., Herman A., Pullen A. M., Kubo R., Kappler J. W., Marrack P. The V beta-specific superantigen staphylococcal enterotoxin B: stimulation of mature T cells and clonal deletion in neonatal mice. Cell. 1989 Jan 13;56(1):27–35. doi: 10.1016/0092-8674(89)90980-x. [DOI] [PubMed] [Google Scholar]
- Wilson R. K., Lai E., Concannon P., Barth R. K., Hood L. E. Structure, organization and polymorphism of murine and human T-cell receptor alpha and beta chain gene families. Immunol Rev. 1988 Jan;101:149–172. doi: 10.1111/j.1600-065x.1988.tb00736.x. [DOI] [PubMed] [Google Scholar]
- Woodland D. L., Happ M. P., Gollob K. J., Palmer E. An endogenous retrovirus mediating deletion of alpha beta T cells? Nature. 1991 Feb 7;349(6309):529–530. doi: 10.1038/349529a0. [DOI] [PubMed] [Google Scholar]
- Woodland D., Happ M. P., Bill J., Palmer E. Requirement for cotolerogenic gene products in the clonal deletion of I-E reactive T cells. Science. 1990 Feb 23;247(4945):964–967. doi: 10.1126/science.1968289. [DOI] [PubMed] [Google Scholar]
- Yanagi Y., Yoshikai Y., Leggett K., Clark S. P., Aleksander I., Mak T. W. A human T cell-specific cDNA clone encodes a protein having extensive homology to immunoglobulin chains. Nature. 1984 Mar 8;308(5955):145–149. doi: 10.1038/308145a0. [DOI] [PubMed] [Google Scholar]
- 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]
- Yoshikai Y., Anatoniou D., Clark S. P., Yanagi Y., Sangster R., Van den Elsen P., Terhorst C., Mak T. W. Sequence and expression of transcripts of the human T-cell receptor beta-chain genes. Nature. 1984 Dec 6;312(5994):521–524. doi: 10.1038/312521a0. [DOI] [PubMed] [Google Scholar]
- von Boehmer H., Kisielow P. Self-nonself discrimination by T cells. Science. 1990 Jun 15;248(4961):1369–1373. doi: 10.1126/science.1972594. [DOI] [PubMed] [Google Scholar]