title: 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.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, School of Medicine, Philadelphia 19104-6082.
authors.forename: K
authors.initials: K
authors.lastname: Yui
authors.forename: A
authors.initials: A
authors.lastname: Bhandoola
authors.forename: M Z
authors.initials: MZ
authors.lastname: Radic
authors.forename: S
authors.initials: S
authors.lastname: Komori
authors.forename: M
authors.initials: M
authors.lastname: Katsumata
authors.forename: M I
authors.initials: MI
authors.lastname: Greene
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000032:analysis; D001327:Autoimmune Diseases / Q000209:etiology; D015551:Autoimmunity; D015704:CD4 Antigens / Q000032:analysis; D016827:CD8 Antigens / Q000032:analysis; D007136:Immunoglobulins / Q000032:analysis; D008213:Lymphocyte Activation; D008232:Lymphoproliferative Disorders / Q000276:immunology*; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D009857:Oncogenes; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics*; D013601:T-Lymphocytes / Q000502:physiology*
chemical_list: D000974:Antibodies, Antinuclear; D015704:CD4 Antigens; D016827:CD8 Antigens; D007136:Immunoglobulins; D016693:Receptors, Antigen, T-Cell, alpha-beta