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CD4+CD25+ T cell-dependent inhibition of autoimmunity in transgenic mice overexpressing human Bcl-2 in T lymphocytes

Gonzalez, Jovanna
Tamayo, Esther
Santiuste, Ines
Marquina, Regina
Buelta, Luis
Gonzalez-Gay, M. A.
Lopez-Hoyos, Marcos
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Published in Journal of Immunology. 2007, vol. 178, no. 5, p. 2778-2786
Abstract Regulation of lymphocyte survival is essential for the maintenance of lymphoid homeostasis preventing the development of autoimmune diseases. Recently, we described a systemic lupus erythematosus associated with an IgA nephropathy in autoimmune-prone (NZW x C57BL/6)F(1) overexpressing human Bcl-2 (hBcl-2) in B cells (transgenic (Tg) 1). In the present study, we analyze in detail a second line of hBcl-2 Tg mice overexpressing the transgene in all B cells and in a fraction of CD4(+) and CD8(+) T cells (Tg2). We demonstrate here that the overexpression of hBcl-2 in T cells observed in Tg2 mice is associated with a resistance to the development of lupus disease and collagen type II-induced arthritis in both (NZW x C57BL/6)F(1) and (DBA/1 x C57BL/6)F(1) Tg2 mice, respectively. The disease-protective effect observed in autoimmune-prone Tg2 mice is accompanied by an increase of peripheral CD4(+)CD25(+) hBcl-2(+) regulatory T cells (T(regs)), expressing glucocorticoid-induced TNFR, CTLA-4, and FoxP3. Furthermore, the in vivo depletion of CD4(+)CD25(+) T(regs) in (DBA/1 x C57BL/6)F(1) Tg2 mice promotes the development of a severe collagen type II-induced arthritis. Taken together, our results indicate that the overexpression of hBcl-2 in CD4(+) T cells alters the homeostatic mechanisms controlling the number of CD4(+)CD25(+) T(regs) resulting in the inhibition of autoimmune diseases.
Keywords AnimalsArthritis, Experimental/*immunology/pathologyAutoimmune Diseases/chemically induced/*immunology/pathology*Autoimmunity/geneticsB-Lymphocytes/immunology/pathologyBiological MarkersCD8-Positive T-Lymphocytes/immunology/pathologyCollagen Type II/toxicityGene ExpressionHomeostasis/immunologyHumansMiceMice, TransgenicProto-Oncogene Proteins c-bcl-2/genetics/*immunologyT-Lymphocytes, Regulatory/*immunology/pathology
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PMID: 17312121
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