Inhibition of abnormal T cell development and autoimmunity in gld mice by transgenic T cell receptor beta chain.

• 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.
• Authors: K Yui, A Bhandoola, M Z Radic, S Komori, M Katsumata, M I Greene (Affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, School of Medicine, Philadelphia 19104-6082.)
• 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)

Chemical References

• Antibodies, Antinuclear
• Antigens, CD4
• Antigens, CD8
• Immunoglobulins
• Receptors, Antigen, T-Cell, alpha-beta

Topics

• Animals
• Antibodies, Antinuclear (analysis)
• Antigens, CD4 (analysis)
• Antigens, CD8 (analysis)
• Autoimmune Diseases (etiology)
• Autoimmunity
• Immunoglobulins (analysis)
• Lymphocyte Activation
• Lymphoproliferative Disorders (immunology)
• Mice
• Mice, Inbred Strains
• Mice, Transgenic
• Oncogenes
• Receptors, Antigen, T-Cell, alpha-beta (genetics)
• T-Lymphocytes (physiology)