J. González

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 × 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.

p27Kip1 inhibits systemic autoimmunity through the control of Treg cell activity and differentiation

OBJECTIVE Despite the importance of Treg cells in the maintenance of immunologic tolerance, the mechanisms that control their generation and activity are unknown. Since the cell cycle inhibitor p27(Kip1) (p27) was involved in T cell anergy, we undertook this study to explore its role in both Treg cell processes. METHODS The development of type II collagen-induced arthritis (CIA) and lupus-like abnormalities was compared between transgenic mice overexpressing human Bcl-2 in T cells (BCL2-TgT mice) and nontransgenic mice that were deficient or not deficient in p27. The contribution of Treg cells to disease evolution was also explored. Finally, the in vitro activity of Treg cells and their differentiation from naive CD4+ cells was compared between these strains of mice. RESULTS BCL2-TgT mice were protected against CIA by a Treg cell-dependent mechanism. In association with this protection, the overexpression of Bcl-2 in T cells enhanced the differentiation and activity of Treg cells. Both Bcl-2 effects were independent of its antiapoptotic activity but dependent on its capacity to induce the expression of p27 that augmented the strength of transforming growth factor β (TGFβ) signaling in T cells. Accordingly, down-modulation of p27 expression in BCL2-TgT mice promoted CIA. In addition, p27 deficiency in aged C57BL/6 mice reduced the number and activity of Treg cells and induced the development of mild lupus-like abnormalities. CONCLUSION Our results point to p27 as a critical regulator of Treg cell differentiation and function through the positive modulation of TGFβ signaling strength in T cells.

GITR contributes to the systemic adjuvanticity of the Escherichia coli heat-labile enterotoxin

The Escherichia coli heat‐labile enterotoxin (LT) possesses a powerful mucosal and systemic adjuvant effect. However, little is known about the cellular and molecular basis of the immunostimulatory activity of LT at the mucosal level, and even less information is available on the mechanisms underlying its systemic adjuvant activity. In this study, we show that distinct mechanisms are responsible for the parenteral and mucosal adjuvanticity of LT. Indeed, the systemic administration of LT upregulates the expression of glucocorticoid‐induced TNFR‐related protein (GITR), but not other activation markers, in naive T cells. Using WT and GITR‐deficient mice and LT and its enzymatically inactive mutant LTK63 as adjuvants, we show that the induction of GITR expression in T cells accounts for the systemic immunostimulatory capacity of LT, which requires an intact enzymatic activity. In contrast, the mucosal administration of LT does not induce GITR expression on Peyers patche T cells and accordingly no differences are observed in the mucosal adjuvanticity of LT between WT and GITR‐deficient mice. Altogether, our results demonstrate the distinct effect of LT after parenteral administration when compared with the mucosal delivery, and describe a new mechanism of LT adjuvanticity related to its ability to induce the expression of GITR in CD4+ T cells.

Abortion in goats by Caprine alphaherpesvirus 1 in Spain

An abortion outbreak occurred in a goat herd of Murciano-Granadina breed in Almeria Region in Spain where 80 pregnant females aborted. All bacteriological and parasitological examinations resulted negative, whereas virological investigations and real-time PCR assay showed the presence of Caprine alphaherpesvirus 1 DNA in the pathological specimens from aborted foetuses. Nucleotide sequence analysis revealed that the DNA was highly close related to the Swiss strain E-CH (99.7%) and a little less extent to the Italian BA.1 strain (99.4%). Histopathological examination revealed multifocal, well-circumscribed, 50- to 200-μm-diameter foci of coagulative necrosis in the liver, lungs and kidneys of three foetuses. In the periphery of the necrosis, there were frequently epithelial cells with the chromatin emarginated by large, round, amphophilic intranuclear viral inclusion bodies. The source of the infection in the herd could not clearly find out even some hypothesis were formulated. This seems to be the first report of an abortion outbreak due to Caprine alphaherpesvirus 1 in a goat herd in Spain.