Abstract
Recent studies have demostrated that the diversity of T-cell receptor alpha (Tcra) gene expression may be confined by a developmental program for gene rearrangement. To examine the effect of age on Tcra gene usage in peripheral tissues, a comparison of Tcr transcripts from newborn and adult mouse splenocytes was made. RNA was first isolated from the spleens of newborn (within five days from birth) and adult B10.BR mice. The polymerase chain reaction was then used to assess the presence of Tcra-V1, Tcra-V2, and Tcra-V3 gene sequences within the two RNA pools. The Tcra-V2 transcript was frequent in both newborn and adult populations and was therefore selected for sequencing analyses, by which V-gene family member and J gene usage could be delineated. Forty-one sequences were obtained, demonstrating Tcra-V2 gene family structure in the B10.BR mouse. Six family members were identified, of which four were new. Although there were differences in gene usage between newborn and adult animals, some junctional diversity added to the repertoire of both populations. A striking feature of V-J joining, as illustrated by this study, was the restriction of combinations based on the J gene location within the Tcra locus. The Tcra-V2 gene of dominant expression in the newborn (B10.BR.6) rearranged exclusively with the 30 most 5'Tcra-J genes. The Tcra-V2 gene of dominant expression at the adult stage (B10.BR.1) rearranged exclusively with the 21 most 3'Tcra-J genes in the locus. Thus, V-J combinatorial diversity was restricted in both newborn and adult mice, yielding a trend from 5'-3' Tcra-J gene usage with age. Inherent restrictions in V-J combinations should now be considered with regard to antigen responsiveness, particularly in the young animal. Qualitative restrictions in Tcr repertoire, compounding low T-cell numbers in peripheral tissues, may well contribute to functional voids and immunodeficiencies in early life.
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References
Alt, F. W. and Baltimore, D.: Joining of Immunoglobulin heavy chain gene segments: Implications from a chromosome with evidence of three D-JH fusions. Proc Natl Acad Sci USA 79: 4118–4122, 1982
Arden, B., Klotz, J. L., Siu, G., and Hood, L. E.: Diversity and structure of genes of the α family of mouse T-cell antigen receptor. Nature 316: 783–787, 1985
Bangs, L. A., Sanz, I. E., and Teale, J. M.: Comparison of D, JH, and junctional diversity in the fetal, adult, and aged B-cell repertoires. J Immunol 146: 1996–2004, 1991
Bill, J., Yague, J., Appel, V. B., White, J., Horn, G., Erlich, H. A., and Palmer, E.: Molecular genetic analysis of 178 I-A-bm12-reactive T cells. J Exp Med 169: 115–133, 1989
Born, W., Yagüe, J., Palmer, E., Kappler, J., and Marrack, P.: Rearrangement of T-cell receptor β-chain genes during T-cell development. Proc Natl Acad Sci USA 82: 2925–2929, 1985
Chien, Y.-H., Becker, D. M., Lindsten, T., Okamura, M., Cohen, D. I., and Davis, M. M.: A third type of murine T-cell receptor gene. Nature 312: 31–35, 1984
Davis, M. M. and Bjorkman, P. J.: T-cell antigen receptor genes and T-cell recognition. Nature 334: 395–402, 1988
Feeney, A. J.: lack of N regions in fetal and neonatal mouse immunoglobulin V-D-J junctional sequences. J Exp Med 172: 1377–1390, 1990
Fink, P. J., Matis, L. A., McElligott, D. L., Bookman, M., and Hedrick, S. M.: Correlations between T-cell specificity and the structure of the antigen receptor. Nature 321: 219–226, 1986
Fondell, J. D., Marolleau, J.-P., Primi, D., and Marcu, K. B.: On the mechanism of non-allelically excluded Vα-Jα T-cell receptor secondary rearrangements in a murine T-cell lymphoma. J Immunol 144: 1094–1103, 1990
Garman, R. D., Doherty, P. J., and Raulet, D. H.: Diversity, rearrangement, and expression of murine T-cell gamma genes. Cell 45: 733–742, 1986
Hue, I., Trucy, J., McCoy, C., Couez, D., Malissen, B., and Malissen, M.: A novel type of aberrant T-cell receptor α-chain gene rearrangement. Im Implications for allelic exclusion and the V-J recombination process. J Immunol 144: 4410–4419, 1990
Hurwitz, J. L., Samaridis, J., and Pelkonen, J.: Immature and advanced patterns of T-cell receptor gene rearrangement among lymphocytes in splenic culture. J Immunol 142: 2533–2539, 1989
Imai, K., Kanno, M., Kimoto, H., Shigemoto, K., Yamamoto, S., and Taniguchi, M.: Sequence and expression of transcripts of the T-cell antigen receptor α-chain gene in a functional, antigen-specific suppressor-T-cell hybridoma. Proc Natl Acad Sci USA 83: 8708–8712, 1986
Iwamoto, A., Ohashi, P. S., Pircher, H., Walker, C. L., Michalopoulos, E. E., Rupp, F., Hengartner, H., and Mak, T. W.: T-cell receptor variable gene usage in a specific cytotoxic T-cell response. J Exp Med 165: 591–600, 1987
Knobloch, C., Goldmann, S. F., and Friedrich, W.: Limited T-cell receptor diversity of transplacentally acquired maternal T cells in severe combined immunodeficiency. J Immunol 146: 4157–4164, 1991
Lafaille, J. J., Decloux, A., Bonneville, M., Takagaki, Y., and Tonegawa, S.: Junctional sequences of T-cell receptor γδ genes: Implications for γδ T-cell lineages and for a novel intermediate of V-(D)-J joining. Cell 59: 859–870, 1989
Lai, M.-Z., Huang, S.-Y., Briner, T. J., Guillet, J.-G., Smith, J. A., and Gefter, M. L.: T-cell receptor gene usage in the response to lambda repressor cI protein. J Exp Med 168: 1081–1097, 1988
Pircher, H., Michalopoulos, E. E., Iwamoto, A., Ohashi, P. S., Baenziger, J., Hengartner, H., Zinkernagel, R. M., and Mak, T. W.: Molecular analysis of the antigen receptor of virus-specific cytotoxic T cells and identification of a new V α family. Eur J Immunol 17: 1843–1846, 1987
Roth, M. E., Holman, P. O., and Kranz, D. M.: Nonrandom use of J α gene segments: Influence of V α and J α gene location. J Immunol 147: 1075–1081, 1991
Saito, H., Kranz, D. M., Takagaki, Y., Hayday, A. C., Eisen, H. N., and Tonegawa, S.: A third rearranged and expressed gene in a clone of cytotoxic T lymphocytes. Nature 312: 36–40, 1984
Sambrook, J., Fritsch, E. F., and Maniatis, T.: Molecular Cloning. A Laboratory Manual. Cold Spring Harbor Laboratory, Cold Spring Harbor, 1989
Schneider, R., Lees, R. K., Pedrazzini, T., Zinkernagel, R. M., Hengartner, H., and MacDonald, H. R.: Postnatal disappearance of self-reactive (V β6+) cells from the thymus of Mls-a mice. J Exp Med 169: 2149–2158, 1989
Schwartz, D. H., Hurwitz, J. L., Greenspan, N. S., and Doherty, P. C.: Priming of virus-immune memory T-cells in newborn mice. Infect Immun 43: 202–205, 1984
Smith, H., Chen, I.-M., Kubo, R., and Tung, K. S. K.: Neonatal thymectomy results in a repertoire enriched in T cells deleted in adult thymus. Science 245: 749–752, 1989
Spinella, D. G., Hansen, T. H., Walsh, W. D., Behlke, M. A., Tillinghast, J. P., Chou, H. S., Whiteley, P. J., Kapp, J. A., Pierce, C. W., Shevach, E. M., and Loh, D. Y.: Receptor diversity of insulin-specific T-cell lines from C57BL (H-2b) mice. J Immunol 138: 3991–3995, 1987
Tan, K.-N., Datlof, B. M., Gilmore, J. A., Kronman, A. C., Lee, J. H., Maxam, A. M., and Rao, A.: The T-cell receptor V α3 gene segment is associated with reactivity to p-azobenzenearsonate. Cell 54: 247–261, 1988
Taylor, A. H., Haberman, A. M., Gerhard, W., and Caton, A. J.: Structure-function relationships among highly diverse T cells that recognize a determinant from influenza virus hemagglutinin. J Exp Med 172: 1643–1651, 1990
Thompson, S. D., Pelkonen, J., and Hurwitz, J. L.: First T-cell receptor α gene rearrangements during T-cell ontogeny skew to the 5'region of the Jα locus. J Immunol 145: 2347–2352, 1990a
Thompson, S. D., Pelkonen, J., Rytkonen, M., Samaridis, J., and Hurwitz, J. L.: Nonrandom rearrangement of T-cell receptor Jα genes in bone marrow T-cell differentiation cultures. J Immunol 144: 2829–2834, 1990b
Thompson, S. D., Manzo, A. R., Pelkonen, J., Larch, M., and Hurwitz, J. L.: Developmental T-cell receptor gene rearrangements: Relatedness of the αβ and γδ T-cell precursor. Eur J Immunol, in press, 1991
Urban, J. L., Kumar, V., Kono, D. H., Gomez, C., Horvath, S. J., Clayton, J., Ando, D. G., Secarz, E. E., and Hood, L.: Restricted use of T-cell receptor V genes in murine autoimmune encephalocyelitis raises possibilities for antibody therapy. Cell 54: 577–592, 1988
Winoto, A., Urban, J. L., Lan, N. C., Goverman, J., Hood, L., and Hansburg, D.: Predominant use of a Vα gene segment in mouse T-cell receptors for cytochrome c. Nature 324: 679–682, 1986
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Eight nucleotide sequences reported in this paper have been submitted to the GenBank nucleotide sequence database and have been assigned the accession numbers M73550-1 and M73761-6.
Address correspondence and offprint requests to: J. L. Hurwitz.
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Thompson, S.D., Larché, M., Manzo, A.R. et al. Diversity of T-cell receptor alpha gene transcripts in the newborn and adult periphery. Immunogenetics 36, 95–103 (1992). https://doi.org/10.1007/BF00215285
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DOI: https://doi.org/10.1007/BF00215285