CD4+CD25+ T Cell-Dependent Inhibition of Autoimmunity in Transgenic Mice Overexpressing Human Bcl-2 in T Lymphocytes

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 × C57BL/6)F1 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 × C57BL/6)F1 and (DBA/1 × C57BL/6)F1 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 (Tregs), expressing glucocorticoid-induced TNFR, CTLA-4, and FoxP3. Furthermore, the in vivo depletion of CD4+CD25+ Tregs in (DBA/1 × C57BL/6)F1 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+ Tregs resulting in the inhibition of autoimmune diseases.

Bcl-xL is required for the development of functional regulatory CD4 cells in lupus-afflicted mice following treatment with a tolerogenic peptide

“…Several studies reported increased expression of Bcl-xL and Bcl-2 in CD4 þ CD25 þ cells but only to explain the superior survival rates or a numerical increase in the latter cells [12,[29][30][31]. In fact, the association between the expression of Bcl-xL and Foxp3 could be indirectly suspected, based on retrospective data.…”

“…Transgenic expression of Bcl-xL or Bcl-2 in murine B cells was shown to modify the repertoire of B cells and to result in the production of pathogenic antibodies and the development of autoimmune diseases including systemic lupus erythematosus (SLE) and the exacerbation of collagen-induced arthritis [7][8][9]. In contrast, when Bcl-2 was transgenically expressed in T cells, the mice were found to be long-lived and without evidence of autoimmunity, and they were also resistant to the development of collagen-induced arthritis and SLE [10][11][12].…”

Mice Deficient in CD38 Develop an Attenuated Form of Collagen Type II-Induced Arthritis

“…In this regard, in our study the anti-CD25 treatment is administered once prior to the induction of CIA instead of the 4 weeks-long treatment initiated 13 days after col II-immunization used by Kelchtermans et al [28]. In addition, the treatment protocol used here has been proved to be able to reverse the protection against CIA in transgenic mice overexpressing human Bcl-2 in T cells [30], further indicating that the lack of exacerbation of CIA in Treg-depleted WT mice is not related to the concomitant possible depletion of pathogenic CD4 cells expressing transitory CD25 after their activation.…”

“…The efficiency of this treatment was evaluated in peripheral blood mononuclear cells by flow cytometry the one day before immunization. Previous studies showed that this treatment was able to reverse the protection against CIA in transgenic mice overexpressing human Bcl-2 in T cells [30]. An evaluation of arthritis severity was performed weekly.…”

B-cell overexpression of Bcl-2 cooperates with p21 deficiency for the induction of autoimmunity and lymphomas

“…B6-SV40-Em-hbcl-2-22 Tg mice (B6-hBcl-2-B Tg) [3] overexpressing hBcl-2 in B cells, B6.129S2-Cdkn1a tm1Tyj /J (B6.p21 À/À ) [22] and B6.129S4-Cdkn1b tm1Mlf /J (B6.p27 À/À ) mice [15] were purchased from The Jackson Laboratories (Bar Harbor, ME). The selection of hBcl-2-B Tg mice was performed by flow cytometry using peripheral blood mononuclear cells and a specific mAb against hBcl-2 (clone 6C8; BD Biosciences, Madrid, Spain), as described previously [23]. B6.p21 À/À -hBcl-2-B Tg and B6.p27 À/À -hBcl-2-B Tg mice were obtained by intercrossing F1 progeny of B6.p21 À/À and B6.p27 À/À mice with B6-hBcl-2-B Tg mice.…”