A B-Cell Superantigen Induces the Apoptosis of Murine and Human Malignant B Cells.

B-cell superantigens (Sags) bind to conserved sites of the VH or VL regions of immunoglobulin molecules outside their complementarity-determining regions causing the apoptosis of normal cognate B cells. No attempts to investigate whether B-cell Sags are able to induce the apoptosis of cognate malignant B cells were reported. In the present study we show that protein L (PpL), secreted by Finegoldia magna, a B-cell Sag which interacts with κ+ bearing cells, induces the apoptosis of murine and human κ+ lymphoma B cells both in vitro and in vivo.

B-cell lymphopoiesis is regulated by cathepsin L.

Cathepsin L (CTSL) is a ubiquitously expressed lysosomal cysteine peptidase with diverse and highly specific functions. The involvement of CTSL in thymic CD4+ T-cell positive selection has been well documented. Using CTSL(nkt/nkt) mice that lack CTSL activity, we have previously demonstrated that the absence of CTSL activity affects the homeostasis of the T-cell pool by decreasing CD4+ cell thymic production and increasing CD8+ thymocyte production.

[Increase of regulatory T cells in the lymph node of cathepsin L mutant mice].

Regulatory CD4+CD25+Foxp3+ T cells (Treg) have been implicated in different pathologies including cancer, infections and autoimmune diseases and in the rejection of allogeneic organ transplantation. Thus, modulation of Treg activity has a great potential in the treatment of these pathologies. Herein, we evaluated the influence of cathepsin L (CTSL) on Treg homeostasis.

[Regulatory T cell depletion increases the number of CD8 cells during mouse mammary tumor virus infection].

Mouse mammary tumor virus (MMTV) is a milk-borne betaretrovirus that has developed strategies to exploit and subvert the host immune system. We have shown in a natural model of MMTV infection that the virus causes early and progressive increases in superantigen (Sag)-specific CD4+ CD25+ Foxp3+ regulatory T cells (Treg) in Peyer's patches. Herein, we evaluated whether the depletion of Treg cells affects the CD8+ population during milk-borne MMTV infection.

Superantigens increase the survival of mice bearing T cell lymphomas by inducing apoptosis of neoplastic cells.

Superantigens bind to major histocompatibility complex class II molecules and interact with T cells expressing a particular T cell receptor Vβ inducing a strong proliferation/deletion response of the superantigen-reactive T cells. However, there have been no attempts to investigate the ability of Sags to induce apoptosis in neoplastic T cells by signaling through the Vβ region of their TCR. In the present study we show that bacterial and MMTV-encoded superantigens induce the apoptosis of AKR/J cognate lymphoma T cells both in vitro and in vivo.

Increases in IgA(+) B cells in Peyer's patches during milk-borne mouse mammary tumor virus infection are influenced by Toll-like receptor 4 and are completely dependent on the superantigen response.

Mouse mammary tumor virus (MMTV) is a milk-borne betaretrovirus that has developed strategies to exploit and subvert the host immune system. Although mammary glands are the final target of infection, Peyer's patches (PP) are the entry site of the virus. Herein, we show that the infection induces increases in the number of PP IgA(+) B cells and higher expression of the α circular transcript, which is a specific marker of the switch to IgA.

Mouse bone marrow-derived mesenchymal stromal cells turn activated macrophages into a regulatory-like profile.

In recent years it has become clear that the therapeutic properties of bone marrow-derived mesenchymal stromal cells (MSC) are related not only to their ability to differentiate into different lineages but also to their capacity to suppress the immune response. We here studied the influence of MSC on macrophage function. Using mouse thioglycolate-elicited peritoneal macrophages (M) stimulated with LPS, we found that MSC markedly suppressed the production of the inflammatory cytokines TNF-alpha, IL-6, IL-12p70 and interferon-gamma while increased the production of IL-10 and IL-12p40.

Detection of human mammary tumor virus proteins in human breast cancer cells.

Mouse mammary tumor virus (MMTV) has been proven to induce mammary cancer in mice. MMTV-like env gene sequences have been detected in one-third of the human breast tumors studied. The whole proviral structure with 95% homology to MMTV was found in two human breast tumors and was designated as human mammary tumor virus (HMTV).

Early increases in superantigen-specific Foxp3+ regulatory T cells during mouse mammary tumor virus infection.

Mouse mammary tumor virus (MMTV) is a milk-borne betaretrovirus that has developed strategies to exploit and subvert the host immune system. Here, we show in a natural model of MMTV infection that the virus causes early and progressive increases in superantigen (SAg)-specific Foxp3(+) regulatory T cells (T(reg)) in Peyer's patches (PP). These increases were shown to be dependent on the presence of dendritic cells.

Characterization of viral particles isolated from primary cultures of human breast cancer cells.

The association of human breast cancer with sequences similar to the mouse mammary tumor virus (MMTV) has been shown, but convincing evidence for the presence of viral particles in breast tumors has been lacking. We have described the complete proviral structure of a retrovirus in human breast cancer. This provirus, designated as human mammary tumor virus (HMTV), was 95% homologous to MMTV and revealed features of a replication-competent virus.

Critical role of dendritic cells in mouse mammary tumor virus in vivo infection.

Mouse mammary tumor virus (MMTV) is a milk-transmitted betaretrovirus that causes mammary tumors in mice. Although mammary epithelial cells are the ultimate targets of MMTV, the virus utilizes components of the host immune system to establish infection. Previous studies indicated that dendritic cells play a role in MMTV infection.

Endogenous glucocorticoids cause thymus atrophy but are protective during acute Trypanosoma cruzi infection.

The cytokine-mediated stimulation of the hypothalamus-pituitary-adrenal (HPA) axis is relevant for survival during bacterial endotoxemia and certain viral infections. However, only limited information is available regarding the effects of endogenous glucocorticoids on parasite diseases. We have studied this issue using, as a model, C57Bl/6 and Balb/c mice infected with Trypanosoma cruzi, the causal agent of Chagas' disease.

Cathepsin-L influences the expression of extracellular matrix in lymphoid organs and plays a role in the regulation of thymic output and of peripheral T cell number.

Nackt mice, which are deficient in cathepsin-L (CTSL), show an early impairment during positive selection in the context of class II MHC molecules and as a consequence, the percentage and absolute number of CD4(+) thymocytes are significantly decreased. In this study, we show that lymph nodes from nackt mice are hypertrophied, showing normal absolute numbers of CD4(+) T cells and marked increases in the number of CD8(+) T lymphocytes. Basal proliferative levels are increased in the CD4(+) but not in the CD8(+) population.

Thymocyte depletion during acute Trypanosoma cruzi infection in C57BL/6 mice is partly reverted by lipopolysaccharide pretreatment.

Infection with Trypanosoma cruzi in C57BL/6 mice leads to a progressive fatal disease accompanied by thymocyte depletion, which is not related with a higher parasite burden but with increased serum levels of tumour necrosis factor alpha (TNF- alpha). Because this situation may result from an excessive inflammatory syndrome, mice were now given anti-TNF-alpha mAbs throughout their acute infection, or subjected to a LPS desensitization protocol before parasite challenge. Treatment with anti-TNF-alpha mAbs failed to ameliorate thymocyte depletion but shortened survival time and increased parasite load.

Toll-like receptor 4-dependent activation of dendritic cells by a retrovirus.

Mouse mammary tumor virus (MMTV) is a milk-borne retrovirus that exploits the adaptive immune system. It has recently been shown that MMTV activates B cells via Toll-like receptor 4 (TLR4), a molecule involved in innate immune responses. Here, we show that direct virus binding to TLR4 induced maturation of bone marrow-derived dendritic cells and up-regulated expression of the MMTV entry receptor (CD71) on these cells.

Origin and progression of pregnancy-dependent mammary tumors induced by new mouse mammary tumor virus variants.

In order to study mechanisms of progression of mouse mammary tumor virus (MMTV)-induced pregnancy-dependent mammary lesions, we removed and serially transplanted 17 small tumors detected in MMTV-infected pregnant females. This gave rise to the same number of 'in vivo' tumor lines. Hormone-dependency of the passages was determined by comparing tumor development in multiparous versus virgin hosts.

Neonatal infection with a milk-borne virus is independent of beta7 integrin- and L-selectin-expressing lymphocytes.

Mouse mammary tumor virus (MMTV) is acquired by neonates through milk and first infects lymphocytes in Peyer's patches. We show here that newborn mice lacking beta7 integrin or L-selectin were infected with MMTV at wild-type levels in both their lymphoid and mammary tissues. Superantigen-mediated activation and cognate T cell deletion were also unimpaired in both types of null mice.