CD4+CD25+ T cell-dependent inhibition of autoimmunity in transgenic mice overexpressing human Bcl-2 in T lymphocytes.
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.
González
Jovanna
J
Departamento de Biología Molecular (Unidad asociada al Centro de Investigaciones Biológicas/Consejo Superior de Investigaciones Científicas), Universidad de Cantabria, Cardenal Herrera Oria s/n, 39011 Santander, Spain.
Tamayo
Esther
E
Santiuste
Inés
I
Marquina
Regina
R
Buelta
Luis
L
González-Gay
Miguel A
MA
Izui
Shozo
S
López-Hoyos
Marcos
M
Merino
Jesús
J
Merino
Ramón
R
D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology* / Q000473:pathology; D001327:Autoimmune Diseases / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D015551:Autoimmunity / Q000235:genetics; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D015415:Biomarkers; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D024043:Collagen Type II / Q000633:toxicity; D015870:Gene Expression; D006706:Homeostasis / Q000276:immunology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology
D015415:Biomarkers; D024043:Collagen Type II; D019253:Proto-Oncogene Proteins c-bcl-2