Abstract |
Mice homozygous for the gld (generalized lymphoproliferative disease) mutation developed systemic autoimmune disease and severe lymphadenopathy due to an age-related accumulation in the peripheral lymphoid organs of polyclonal T cells bearing a unique phenotype (CD4-CD8- TCR alpha beta+B220+). These T cells overexpress T cell receptor ( TcR) alpha beta chain RNA, proto-oncogenes c-myb and fyn, and proliferate poorly in response to TcR-mediated stimulation. The origin of these T cells is poorly understood. To study the influence of a functionally rearranged TcR beta chain on the T cell developmental abnormality of the gld mutation and autoimmunity, we have backcrossed TcR V beta 8.1-transgenic mice to C3H-gld/gld to homozygosity (transgenic gld mice). In transgenic gld mice, lymphadenopathy was markedly inhibited and the accumulation of CD4-CD8- T cells did not occur, although the remaining T cells overexpressed c-myb and proliferated poorly in response to TcR occupancy. These features indicate that the pattern of proto-oncogene expression and abnormal function persist in phenotypically normal T cells in transgenic gld mice, and that these characteristics can be dissociated from the accumulation of CD4-CD8- T cells. The hypergammaglobulinemia and anti- double-stranded DNA ( anti-dsDNA) antibody production was partially improved in transgenic gld mice, supporting the critical role of T cells in abnormal B cell activation described in autoimmunity-prone mice. To investigate further the mechanisms underlying the inhibition of CD4-CD8- T cell accumulation in transgenic gld mice, the fetal ontogeny of T cells in transgenic mice was compared with that of non-transgenic mice. In transgenic thymus, development of TcR alpha beta+ cells was accelerated as detected by earlier expression of CD4, CD8 and TcR in fetal thymus. In contrast, the number of TcR gamma delta+ cells was reduced. We suggest that altered T cell development in transgenic mice directly or indirectly inhibits the accumulation of abnormal T cells in gld mice.
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Authors | K Yui, A Bhandoola, M Z Radic, S Komori, M Katsumata, M I Greene |
Journal | European journal of immunology
(Eur J Immunol)
Vol. 22
Issue 7
Pg. 1693-700
(Jul 1992)
ISSN: 0014-2980 [Print] Germany |
PMID | 1385574
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antibodies, Antinuclear
- CD4 Antigens
- CD8 Antigens
- Immunoglobulins
- Receptors, Antigen, T-Cell, alpha-beta
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Topics |
- Animals
- Antibodies, Antinuclear
(analysis)
- Autoimmune Diseases
(etiology)
- Autoimmunity
- CD4 Antigens
(analysis)
- CD8 Antigens
(analysis)
- Immunoglobulins
(analysis)
- Lymphocyte Activation
- Lymphoproliferative Disorders
(immunology)
- Mice
- Mice, Inbred Strains
- Mice, Transgenic
- Oncogenes
- Receptors, Antigen, T-Cell, alpha-beta
(genetics)
- T-Lymphocytes
(physiology)
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