Abstract
Congenitally thymusless nude mice that lacked functional T cells were reconstituted with H-2-compatible or -incompatible thymus grafts taken from either fetal, newborn, or adult mice and transplanted under the kidney capsule or subcutaneously. Transplantation with unirradiated fetal (15--17 d) or newborn thymus grafts reconstituted the nude mice as assessed by their subsequent generation of virus-specific cytotoxic T cells in vivo or alloreactive T cells in vitro. The restriction specificity of T cells from homozygous mice was exclusively for the nude host H-2, as shown by direct cytolysis or by cold target competitive inhibition assays. irrespective of whether nude mice were reconstituted with H-2-compatible, semiallogeneic, or H-2-incompatible, unirradiated newborn or fetal thymus grafts (in order of decreasing efficiency of reconstitution). The restriction specificity for the nonhost H-2 of the thymus could not be demonstrated even after primary or secondary sensitization in an infected appropriate F1 environment. These nude mice reconstituted with fetal or newborn grafts were tolerant to the H-2 of the thymus donors. Nude mice transplanted with irradiated adult thymus grafts were reconstituted functionally with syngeneic or semisyngeneic but not with allogeneic thymus grafts. In homozygous nu/nu irradiated heterozygous recipients of F1 thymus grafts, the restriction specificity for the nonhost thymic H-2 could not be elicited upon adoptive sensitization in irradiated and infected F1 heterozygote stimulator mice; in fact, these chimeras' lymphocytes were not tolerant to the nonhost H-2. The discrepancy between the restorative capacity of unirradiated vs. irradiated thymus grafts suggests that precursors of T cells in nude mice can acquire restriction specificity and immunocompetence independently of a conventional, functioning H-2-compatible thymus if exposed to an allogeneic fetal or a newborn thymus that contains functioning thymocytes of donor type but not if reconstituted with an irradiated adult allogeneic thymus.
Full Text
The Full Text of this article is available as a PDF (1.5 MB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Binz H., Wigzell H. Antigen-binding, idiotypic T-lymphocyte receptors. Contemp Top Immunobiol. 1977;7:113–177. doi: 10.1007/978-1-4684-3054-7_4. [DOI] [PubMed] [Google Scholar]
- Callahan G. N., Ferrone S., Poulik M. D., Reisfeld R. A., Klein J. Characterization of Ia antigens in mouse serum. J Immunol. 1976 Oct;117(4):1351–1355. [PubMed] [Google Scholar]
- Chesebro B. W., Mitchell G. F., Grumet F. C., Herzenberg L. A., McDevitt H. O., Wegmann T. G. Cell transfer studies in a genetically controlled immune response. Eur J Immunol. 1972 Jun;2(3):243–248. doi: 10.1002/eji.1830020310. [DOI] [PubMed] [Google Scholar]
- Davies A. J. The thymus and the cellular basis of immunity. Transplant Rev. 1969;1:43–91. doi: 10.1111/j.1600-065x.1969.tb00136.x. [DOI] [PubMed] [Google Scholar]
- Fink P. J., Bevan M. J. H-2 antigens of the thymus determine lymphocyte specificity. J Exp Med. 1978 Sep 1;148(3):766–775. doi: 10.1084/jem.148.3.766. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gardner I., Bowern N. A., Blanden R. V. Cell-mediated cytotoxicity against ectromelia virus-infected target cells. I. Specificity and kinetics. Eur J Immunol. 1974 Feb;4(2):63–67. doi: 10.1002/eji.1830040202. [DOI] [PubMed] [Google Scholar]
- Gillis S., Union N. A., Baker P. E., Smith K. A. The in vitro generation and sustained culture of nude mouse cytolytic T-lymphocytes. J Exp Med. 1979 Jun 1;149(6):1460–1476. doi: 10.1084/jem.149.6.1460. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hedrick S. M., Watson J. Genetic control of the immune response to collagen. II. Antibody responses produced in fetal liver restored radiation chimeras and thymus reconstituted F1 hybrid nude mice. J Exp Med. 1979 Sep 19;150(3):646–652. doi: 10.1084/jem.150.3.646. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jerne N. K. The somatic generation of immune recognition. Eur J Immunol. 1971 Jan;1(1):1–9. doi: 10.1002/eji.1830010102. [DOI] [PubMed] [Google Scholar]
- Joklik W. K. The poxviruses. Bacteriol Rev. 1966 Mar;30(1):33–66. doi: 10.1128/br.30.1.33-66.1966. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kappler J. W., Marrack P. The role of H-2 linked genes in helper T-cell function. IV. Importance of T-cell genotype and host environment in I-region and Ir gene expression. J Exp Med. 1978 Dec 1;148(6):1510–1522. doi: 10.1084/jem.148.6.1510. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Katz D. H., Katz L. R., Bogowitz C. A., Skidmore B. J. Adaptive differentiation of murine lymphocytes. II. The thymic microenvironment does not restrict the cooperative partner cell preference of helper T cells differentiating in F1 leads to F1 thymic chimeras. J Exp Med. 1979 Jun 1;149(6):1360–1370. doi: 10.1084/jem.149.6.1360. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Katz D. H. The allogeneic effect on immune responses: model for regulatory influences of T lymphocytes on the immune system. Transplant Rev. 1972;12:141–179. doi: 10.1111/j.1600-065x.1972.tb00055.x. [DOI] [PubMed] [Google Scholar]
- Kindred B. Effect of thymus donor strain on the response of reconstituted nude mice to GLT. Dev Comp Immunol. 1977 Jul;1(3):271–278. doi: 10.1016/s0145-305x(77)80036-0. [DOI] [PubMed] [Google Scholar]
- Kindred B. Functional activity of T cells which differentiate from nude mouse precursors in a congenic or allogeneic thymus graft. Immunol Rev. 1978;42:60–75. doi: 10.1111/j.1600-065x.1978.tb00258.x. [DOI] [PubMed] [Google Scholar]
- Kindred B., Loor F. Activity of host-derived T cells which differentiate in nude mice grafted with co-isogenic or allogeneic thymuses. J Exp Med. 1974 May 1;139(5):1215–1227. doi: 10.1084/jem.139.5.1215. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kindred B. Nude mice in immunology. Prog Allergy. 1979;26:137–238. [PubMed] [Google Scholar]
- Koszinowski U., Ertl H. Role of early viral surface antigens in cellular immune response to vaccinia virus. Eur J Immunol. 1976 Oct;6(10):679–683. doi: 10.1002/eji.1830061004. [DOI] [PubMed] [Google Scholar]
- Lafferty K. J., Woolnough J. The origin and mechanism of the allograft reaction. Immunol Rev. 1977;35:231–262. doi: 10.1111/j.1600-065x.1977.tb00241.x. [DOI] [PubMed] [Google Scholar]
- Lafferty K., Ryan M., Misko I. An improved system for the assay of stimulation in mouse mixed leucocyte cultures. J Immunol Methods. 1974 Mar;4(2):263–273. doi: 10.1016/0022-1759(74)90069-6. [DOI] [PubMed] [Google Scholar]
- Loor F., Hägg L. B. The restoration of the T-lymphoid system of nude mice: lower efficiency of nonlymphoid, epithelial thymus grafts. Cell Immunol. 1977 Mar 1;29(1):200–209. doi: 10.1016/0008-8749(77)90289-1. [DOI] [PubMed] [Google Scholar]
- Loor F., Kindred B., Hägg L. B. Incomplete restoration of T-cell reactivity in nude mice after neonatal allogeneic thymus grafting. Cell Immunol. 1976 Sep;26(1):29–46. doi: 10.1016/0008-8749(76)90345-2. [DOI] [PubMed] [Google Scholar]
- Miller J. F., Gamble J., Mottram P., Smith F. I. Influence of thymus genotype on acquisition of responsiveness in delayed-type hypersensitivity. Scand J Immunol. 1979;9(1):29–38. doi: 10.1111/j.1365-3083.1979.tb02703.x. [DOI] [PubMed] [Google Scholar]
- Miller J. F., Osoba D. Current concepts of the immunological function of the thymus. Physiol Rev. 1967 Jul;47(3):437–520. doi: 10.1152/physrev.1967.47.3.437. [DOI] [PubMed] [Google Scholar]
- Nabholz M., Young H., Rynbeek A., Boccardo R., David C. S., Meo T., Miggiano V., Shreffler D. C. I-region-associated determinants: expression on mitogen-stimulated lymphocytes and detection by cytotoxic T cells. Eur J Immunol. 1975 Sep;5(9):594–599. doi: 10.1002/eji.1830050903. [DOI] [PubMed] [Google Scholar]
- Parks D. E., Doyle M. V., Weigle W. O. Effect of lipopolysaccharide on immunogenicity and tolerogenicity of HGG in C57BL/6J nude mice: evidence for a possible B cell deficiency. J Immunol. 1977 Dec;119(6):1923–1932. [PubMed] [Google Scholar]
- Pfizenmaier K., Strazinski-Powitz A., Rodt H., Röllinghoff M., Wagner H. Virus and trinitrophenol hapten-specific T-cell-mediated cytotoxicity against H-2 incompatible target cells. J Exp Med. 1976 Apr 1;143(4):999–1004. doi: 10.1084/jem.143.4.999. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Pulkkinen A. J., Pfau C. J. Plaque size heterogeneity: a genetic trait of lymphocytic choriomeningitis virus. Appl Microbiol. 1970 Jul;20(1):123–128. doi: 10.1128/am.20.1.123-128.1970. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Radov L. A., Sussdorf D. H., McCann R. L. Relationship between age of allogeneic thymus donor and immunological restoration of athymic ('nude") mice. Immunology. 1975 Dec;29(6):977–988. [PMC free article] [PubMed] [Google Scholar]
- Ramseier H., Lindenmann J. F1 hybrid animals: reactivity against recognition structures of parental strain lymphoid cells. Pathol Microbiol (Basel) 1969;34(6):379–387. doi: 10.1159/000162189. [DOI] [PubMed] [Google Scholar]
- Tyan M. L., McDevitt H. O. Antibody responses to two synthetic polypeptides: the role of the thymic epithelial reticulum. J Immunol. 1970 Nov;105(5):1190–1193. [PubMed] [Google Scholar]
- Waldmann H., Pope H., Beetles C., Davies A. J. The influence of thymus on the development of MHC restrictions exhibited by T-helper cells. Nature. 1979 Jan 11;277(5692):137–138. doi: 10.1038/277137a0. [DOI] [PubMed] [Google Scholar]
- Wortis H. H. Immunological responses of 'nude' mice. Clin Exp Immunol. 1971 Feb;8(2):305–317. [PMC free article] [PubMed] [Google Scholar]
- Zinkernagel R. M., Althage A., Callahan G. Thymic reconstitution of nude F1 mice with one or both parental thymus grafts. J Exp Med. 1979 Sep 19;150(3):693–697. doi: 10.1084/jem.150.3.693. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zinkernagel R. M., Althage A., Cooper S., Callahan G., Klein J. In irradiation chimeras, K or D regions of the chimeric host, not of the donor lymphocytes, determine immune responsiveness of antiviral cytotoxic T cells. J Exp Med. 1978 Sep 1;148(3):805–810. doi: 10.1084/jem.148.3.805. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zinkernagel R. M., Althage A., Cooper S., Kreeb G., Klein P. A., Sefton B., Flaherty L., Stimpfling J., Shreffler D., Klein J. Ir-genes in H-2 regulate generation of anti-viral cytotoxic T cells. Mapping to K or D and dominance of unresponsiveness. J Exp Med. 1978 Aug 1;148(2):592–606. doi: 10.1084/jem.148.2.592. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zinkernagel R. M., Callahan G. N., Althage A., Cooper S., Klein P. A., Klein J. On the thymus in the differentiation of "H-2 self-recognition" by T cells: evidence for dual recognition? J Exp Med. 1978 Mar 1;147(3):882–896. doi: 10.1084/jem.147.3.882. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zinkernagel R. M., Callahan G. N., Althage A., Cooper S., Streilein J. W., Klein J. The lymphoreticular system in triggering virus plus self-specific cytotoxic T cells: evidence for T help. J Exp Med. 1978 Mar 1;147(3):897–911. doi: 10.1084/jem.147.3.897. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zinkernagel R. M., Doherty P. C. Immunological surveillance against altered self components by sensitised T lymphocytes in lymphocytic choriomeningitis. Nature. 1974 Oct 11;251(5475):547–548. doi: 10.1038/251547a0. [DOI] [PubMed] [Google Scholar]
- Zinkernagel R. M., Doherty P. C. MHC-restricted cytotoxic T cells: studies on the biological role of polymorphic major transplantation antigens determining T-cell restriction-specificity, function, and responsiveness. Adv Immunol. 1979;27:51–177. doi: 10.1016/s0065-2776(08)60262-x. [DOI] [PubMed] [Google Scholar]
- Zinkernagel R. M. H-2 restriction of virus-specific T-cell-mediated effector functions in vivo. II. Adoptive transfer of delayed-type hypersensitivity to murine lymphocytic choriomeningits virus is restriced by the K and D region of H-2. J Exp Med. 1976 Sep 1;144(3):776–787. doi: 10.1084/jem.144.3.776. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zinkernagel R. M. H-2 restriction of virus-specific cytotoxicity across the H-2 barrier. Separate effector T-cell specificities are associated with self-H-2 and with the tolerated allogeneic H-2 in chimeras. J Exp Med. 1976 Oct 1;144(4):933–945. doi: 10.1084/jem.144.4.933. [DOI] [PMC free article] [PubMed] [Google Scholar]
- von Boehmer H., Haas W., Jerne N. K. Major histocompatibility complex-linked immune-responsiveness is acquired by lymphocytes of low-responder mice differentiating in thymus of high-responder mice. Proc Natl Acad Sci U S A. 1978 May;75(5):2439–2442. doi: 10.1073/pnas.75.5.2439. [DOI] [PMC free article] [PubMed] [Google Scholar]
- von Boehmer H., Sprent J. T cell function in bone marrow chimeras: absence of host-reactive T cells and cooperation of helper T cells across allogeneic barriers. Transplant Rev. 1976;29:3–23. doi: 10.1111/j.1600-065x.1976.tb00195.x. [DOI] [PubMed] [Google Scholar]