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Induction of autoimmune disease in mice by germline alteration of the T cell receptor gene expression.
J Immunol. 1994 Feb 01; 152(3):1471-84.JI

Abstract

Germline expression of rearranged TCR alpha-chain transgenes with the Ig H chain enhancer reproducibly elicits T cell-mediated autoimmune disease in the thyroid gland, gastric mucosa, Langerhans islets, salivary gland, ovaries, and testes in selected strains of normal mice. Multiple organs are destroyed in a single transgenic mouse and the same organ in transgenic strains with different MHC background, suggesting the transgene expression can elicit self-reactive T cell clones having different Ag specificities and MHC restrictions. Construction of this autoimmune-inducing TCR alpha EH transgene does not require particular V alpha J alpha gene segments or Ag specificities. Moreover, the autoimmune disease can be adoptively transferred to syngeneic normal mice by T cells expressing endogenous TCR alpha-chains. Taken together, these results indicate that the TCR alpha EH transgene expression does not suppress endogenous alpha-chain gene rearrangement and may trigger the expansion/activation of various self-reactive T cells expressing endogenous TCR alpha- and beta-chains. Furthermore, it appears that the transgene-induced autoimmune T cells are not deleted in the normal thymus or rendered anergic upon contact with the normal target self Ag, but can be controlled by a T cell-dependent mechanism, since transfer of the transgenic bone marrow cells to histocompatible SCID mice produces the same autoimmune disease as in the donors, and the autoimmune development in the SCID mice is effectively prevented by co-transfer of syngeneic nontransgenic T cells. This novel autoimmune model produced by genetic manipulation of the T cell lineage, not the target self Ag or the environment of T cell differentiation/selection, should be useful for elucidating the immunologic and genetic basis of autoimmune disease.

Authors+Show Affiliations

Institute of Physical and Chemical Research, Tsukuba Life Science Center, Ibaraki, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

7905503

Citation

Sakaguchi, S, et al. "Induction of Autoimmune Disease in Mice By Germline Alteration of the T Cell Receptor Gene Expression." Journal of Immunology (Baltimore, Md. : 1950), vol. 152, no. 3, 1994, pp. 1471-84.
Sakaguchi S, Ermak TH, Toda M, et al. Induction of autoimmune disease in mice by germline alteration of the T cell receptor gene expression. J Immunol. 1994;152(3):1471-84.
Sakaguchi, S., Ermak, T. H., Toda, M., Berg, L. J., Ho, W., Fazekas de St Groth, B., Peterson, P. A., Sakaguchi, N., & Davis, M. M. (1994). Induction of autoimmune disease in mice by germline alteration of the T cell receptor gene expression. Journal of Immunology (Baltimore, Md. : 1950), 152(3), 1471-84.
Sakaguchi S, et al. Induction of Autoimmune Disease in Mice By Germline Alteration of the T Cell Receptor Gene Expression. J Immunol. 1994 Feb 1;152(3):1471-84. PubMed PMID: 7905503.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Induction of autoimmune disease in mice by germline alteration of the T cell receptor gene expression. AU - Sakaguchi,S, AU - Ermak,T H, AU - Toda,M, AU - Berg,L J, AU - Ho,W, AU - Fazekas de St Groth,B, AU - Peterson,P A, AU - Sakaguchi,N, AU - Davis,M M, PY - 1994/2/1/pubmed PY - 1994/2/1/medline PY - 1994/2/1/entrez SP - 1471 EP - 84 JF - Journal of immunology (Baltimore, Md. : 1950) JO - J. Immunol. VL - 152 IS - 3 N2 - Germline expression of rearranged TCR alpha-chain transgenes with the Ig H chain enhancer reproducibly elicits T cell-mediated autoimmune disease in the thyroid gland, gastric mucosa, Langerhans islets, salivary gland, ovaries, and testes in selected strains of normal mice. Multiple organs are destroyed in a single transgenic mouse and the same organ in transgenic strains with different MHC background, suggesting the transgene expression can elicit self-reactive T cell clones having different Ag specificities and MHC restrictions. Construction of this autoimmune-inducing TCR alpha EH transgene does not require particular V alpha J alpha gene segments or Ag specificities. Moreover, the autoimmune disease can be adoptively transferred to syngeneic normal mice by T cells expressing endogenous TCR alpha-chains. Taken together, these results indicate that the TCR alpha EH transgene expression does not suppress endogenous alpha-chain gene rearrangement and may trigger the expansion/activation of various self-reactive T cells expressing endogenous TCR alpha- and beta-chains. Furthermore, it appears that the transgene-induced autoimmune T cells are not deleted in the normal thymus or rendered anergic upon contact with the normal target self Ag, but can be controlled by a T cell-dependent mechanism, since transfer of the transgenic bone marrow cells to histocompatible SCID mice produces the same autoimmune disease as in the donors, and the autoimmune development in the SCID mice is effectively prevented by co-transfer of syngeneic nontransgenic T cells. This novel autoimmune model produced by genetic manipulation of the T cell lineage, not the target self Ag or the environment of T cell differentiation/selection, should be useful for elucidating the immunologic and genetic basis of autoimmune disease. SN - 0022-1767 UR - https://www.unboundmedicine.com/medline/citation/7905503/Induction_of_autoimmune_disease_in_mice_by_germline_alteration_of_the_T_cell_receptor_gene_expression_ L2 - http://www.jimmunol.org/cgi/pmidlookup?view=long&pmid=7905503 DB - PRIME DP - Unbound Medicine ER -