Abstract
In contrast to broadly expressed classical class I antigens of the major histocompatibility complex, structurally closely related TL antigens are expressed in a highly restricted fashion. Unlike classical class I antigens, TL antigens are not known to be targets of cytotoxic T cells or to mediate graft rejection. Whereas classical class I antigens function as antigen-presenting molecules to T cell receptors (TCR), the role of TL is yet to be defined. To elucidate the function of TL, we have derived transgenic mice expressing TL in most tissues including skin by introducing a TL gene, T3b of C57BL/6 mouse origin, driven by the H-2Kb promoter. By grafting the skin of transgenic mice, we demonstrate that TL can serve as a transplantation antigen and mediate a TCR-alpha/beta+ CD8+ cytotoxic T cell response. This T cell recognition of TL does not require antigen presentation by H-2 molecules. Furthermore, we show that C57BL/6 F1 mice develop CD8+ T cells that are cytotoxic for C57BL/6 TL+ leukemia cells, providing further support for the concept that aberrantly expressed nonmutated proteins such as TL can be recognized as tumor antigens.
Full Text
The Full Text of this article is available as a PDF (980.7 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Bjorkman P. J., Saper M. A., Samraoui B., Bennett W. S., Strominger J. L., Wiley D. C. Structure of the human class I histocompatibility antigen, HLA-A2. Nature. 1987 Oct 8;329(6139):506–512. doi: 10.1038/329506a0. [DOI] [PubMed] [Google Scholar]
- Bjorkman P. J., Saper M. A., Samraoui B., Bennett W. S., Strominger J. L., Wiley D. C. The foreign antigen binding site and T cell recognition regions of class I histocompatibility antigens. Nature. 1987 Oct 8;329(6139):512–518. doi: 10.1038/329512a0. [DOI] [PubMed] [Google Scholar]
- Bluestone J. A., Cron R. Q., Barrett T. A., Houlden B., Sperling A. I., Dent A., Hedrick S., Rellahan B., Matis L. A. Repertoire development and ligand specificity of murine TCR gamma delta cells. Immunol Rev. 1991 Apr;120:5–33. doi: 10.1111/j.1600-065x.1991.tb00585.x. [DOI] [PubMed] [Google Scholar]
- Boyse E. A. The biology of Tla. Cell. 1984 Aug;38(1):1–2. doi: 10.1016/0092-8674(84)90518-x. [DOI] [PubMed] [Google Scholar]
- Campbell R. D., Trowsdale J. Map of the human MHC. Immunol Today. 1993 Jul;14(7):349–352. doi: 10.1016/0167-5699(93)90234-C. [DOI] [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]
- Chen Y. T., Obata Y., Stockert E., Takahashi T., Old L. J. Tla-region genes and their products. Immunol Res. 1987;6(1-2):30–45. doi: 10.1007/BF02918102. [DOI] [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]
- Elliott T. J., Eisen H. N. Cytotoxic T lymphocytes recognize a reconstituted class I histocompatibility antigen (HLA-A2) as an allogeneic target molecule. Proc Natl Acad Sci U S A. 1990 Jul;87(13):5213–5217. doi: 10.1073/pnas.87.13.5213. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Elson C. O., Reilly R. W., Rosenberg I. H. Small intestinal injury in the graft versus host reaction: an innocent bystander phenomenon. Gastroenterology. 1977 May;72(5 Pt 1):886–889. [PubMed] [Google Scholar]
- Fischer Lindahl K., Hermel E., Loveland B. E., Wang C. R. Maternally transmitted antigen of mice: a model transplantation antigen. Annu Rev Immunol. 1991;9:351–372. doi: 10.1146/annurev.iy.09.040191.002031. [DOI] [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]
- Flaherty L., Elliott E., Tine J. A., Walsh A. C., Waters J. B. Immunogenetics of the Q and TL regions of the mouse. Crit Rev Immunol. 1990;10(2):131–175. [PubMed] [Google Scholar]
- Hamasima N., Takahashi T., Taguchi O., Nishizuka Y., Stockert E., Old L. J., Obata Y. Expression of TL, H-2, and chimeric H-2/TL genes in transgenic mice: abnormal thymic differentiation and T-cell lymphomas in a TL transgenic strain. Proc Natl Acad Sci U S A. 1989 Oct;86(20):7995–7999. doi: 10.1073/pnas.86.20.7995. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Heath W. R., Kane K. P., Mescher M. F., Sherman L. A. Alloreactive T cells discriminate among a diverse set of endogenous peptides. Proc Natl Acad Sci U S A. 1991 Jun 15;88(12):5101–5105. doi: 10.1073/pnas.88.12.5101. [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]
- Jenkins R. N., Aldrich C. J., Landolfi N. F., Rich R. R. Correlation of Qa-1 determinants defined by antisera and by cytotoxic T lymphocytes. Immunogenetics. 1985;21(3):215–225. doi: 10.1007/BF00375374. [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]
- Loveland B., Wang C. R., Yonekawa H., Hermel E., Lindahl K. F. Maternally transmitted histocompatibility antigen of mice: a hydrophobic peptide of a mitochondrially encoded protein. Cell. 1990 Mar 23;60(6):971–980. doi: 10.1016/0092-8674(90)90345-f. [DOI] [PubMed] [Google Scholar]
- MacDonald T. T., Ferguson A. Hypersensitivity reactions in the small intestine. III. The effects of allograft rejection and of graft-versus-host disease on epithelial cell kinetics. Cell Tissue Kinet. 1977 Jul;10(4):301–312. [PubMed] [Google Scholar]
- Man S., Salter R. D., Engelhard V. H. Role of endogenous peptide in human alloreactive cytotoxic T cell responses. Int Immunol. 1992 Mar;4(3):367–375. doi: 10.1093/intimm/4.3.367. [DOI] [PubMed] [Google Scholar]
- Matzinger P., Bevan M. J. Hypothesis: why do so many lymphocytes respond to major histocompatibility antigens? Cell Immunol. 1977 Mar 1;29(1):1–5. doi: 10.1016/0008-8749(77)90269-6. [DOI] [PubMed] [Google Scholar]
- Mellor A. L., Tomlinson P. D., Antoniou J., Chandler P., Robinson P., Felstein M., Sloan J., Edwards A., O'Reilly L., Cooke A. Expression and function of Qa-2 major histocompatibility complex class I molecules in transgenic mice. Int Immunol. 1991 May;3(5):493–502. doi: 10.1093/intimm/3.5.493. [DOI] [PubMed] [Google Scholar]
- Müllbacher A., Hill A. B., Blanden R. V., Cowden W. B., King N. J., Hla R. T. Alloreactive cytotoxic T cells recognize MHC class I antigen without peptide specificity. J Immunol. 1991 Sep 15;147(6):1765–1772. [PubMed] [Google Scholar]
- Nakajima-Iijima S., Hamada H., Reddy P., Kakunaga T. Molecular structure of the human cytoplasmic beta-actin gene: interspecies homology of sequences in the introns. Proc Natl Acad Sci U S A. 1985 Sep;82(18):6133–6137. doi: 10.1073/pnas.82.18.6133. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nakayama E., Uenaka A., DeLeo A. B., Stockert E., Obata Y., Ueda R., Inui Y. Molecular basis of a unique tumor antigen of radiation leukemia virus-induced leukemia B6RV2: its relation to MuLV gp70 of xenotropic class. J Immunol. 1986 May 1;136(9):3502–3507. [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]
- Obata Y., Taguchi O., Matsudaira Y., Hasegawa H., Hamasima N., Takahashi T. Abnormal thymic development, impaired immune function and gamma delta T cell lymphomas in a TL transgenic mouse strain. J Exp Med. 1991 Aug 1;174(2):351–362. doi: 10.1084/jem.174.2.351. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Old L. J., Stockert E. Immunogenetics of cell surface antigens of mouse leukemia. Annu Rev Genet. 1977;11:127–160. doi: 10.1146/annurev.ge.11.120177.001015. [DOI] [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]
- Rötzschke O., Falk K., Faath S., Rammensee H. G. On the nature of peptides involved in T cell alloreactivity. J Exp Med. 1991 Nov 1;174(5):1059–1071. doi: 10.1084/jem.174.5.1059. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rötzschke O., Falk K., Stevanović S., Grahovac B., Soloski M. J., Jung G., Rammensee H. G. Qa-2 molecules are peptide receptors of higher stringency than ordinary class I molecules. Nature. 1993 Feb 18;361(6413):642–644. doi: 10.1038/361642a0. [DOI] [PubMed] [Google Scholar]
- Seo N., Okazaki T., Nakanishi-Ito C., Tanino T., Matsudaira Y., Takahashi T., Egawa K. Expression of the Qa-2k phenotype encoded by the Q5k gene on the surface of tumor cells derived from H-2k mice. J Exp Med. 1992 Mar 1;175(3):647–654. doi: 10.1084/jem.175.3.647. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Shawar S. M., Cook R. G., Rodgers J. R., Rich R. R. Specialized functions of MHC class I molecules. I. An N-formyl peptide receptor is required for construction of the class I antigen Mta. J Exp Med. 1990 Mar 1;171(3):897–912. doi: 10.1084/jem.171.3.897. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Simister N. E., Mostov K. E. An Fc receptor structurally related to MHC class I antigens. Nature. 1989 Jan 12;337(6203):184–187. doi: 10.1038/337184a0. [DOI] [PubMed] [Google Scholar]
- Steinmetz M., Winoto A., Minard K., Hood L. Clusters of genes encoding mouse transplantation antigens. Cell. 1982 Mar;28(3):489–498. doi: 10.1016/0092-8674(82)90203-3. [DOI] [PubMed] [Google Scholar]
- Vidović D., Roglić M., McKune K., Guerder S., MacKay C., Dembić Z. Qa-1 restricted recognition of foreign antigen by a gamma delta T-cell hybridoma. Nature. 1989 Aug 24;340(6235):646–650. doi: 10.1038/340646a0. [DOI] [PubMed] [Google Scholar]
- Wu M., van Kaer L., Itohara S., Tonegawa S. Highly restricted expression of the thymus leukemia antigens on intestinal epithelial cells. J Exp Med. 1991 Jul 1;174(1):213–218. doi: 10.1084/jem.174.1.213. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Yokoyama K., Stockert E., Old L. J., Nathenson S. G. Structural comparisons of TL antigens derived from normal and leukemia cells of Tl+ and TL- strains and relationship to genetically linked H-2 major histocompatibility complex products. Proc Natl Acad Sci U S A. 1981 Nov;78(11):7078–7082. doi: 10.1073/pnas.78.11.7078. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Yokoyama K., Stockert E., Old L. J., Nathenson S. G. Structural evidence that the small subunit found associated with the TL antigen is beta 2-microglobulin. Immunogenetics. 1982;15(6):543–549. doi: 10.1007/BF00347048. [DOI] [PubMed] [Google Scholar]