In Vivo and in Absence of a Thymus, the Enforced Expression of the Notch Ligands Delta-1 or Delta-4 Promotes T Cell Development with Specific Unique Effects

Abstract

Heat-killed Brucella abortus (HBa) has been proposed as a carrier for therapeutic vaccines for individuals with immunodeficiency, due to its abilities to induce interleukin-2 (IL-2) and gamma interferon (IFN-␥) in both CD4؉ and CD8 ؉ T cells and to upregulate antigen-presenting cell functions (including IL-12 production). In the current study, we investigated the ability of HBa or lipopolysaccharide isolated from HBa (LPS-Ba) to elicit ␤-chemokines, known to bind to the human immunodeficiency virus type 1 (HIV-1) coreceptor CCR5 and to block viral cell entry. It was found that human peripheral blood mononuclear cells secreted ␤-chemokines following stimulation with HBa, and this effect could not be blocked by anti-IFN-␥ neutralizing antibodies. Among purified T cells, macrophage inflammatory protein 1␣ and 1␤ (MIP-1␣ and MIP-1␤, respectively) secretion was observed primarily in human CD8؉ T cells. The kinetics of ␤-chemokine induction in T cells were slow (3 to 4 days). The majority of ␤-chemokine-producing CD8 ؉ T cells also produced IFN-␥ following HBa stimulation, as determined by triple-color intracellular staining. A significant number of CD8 ؉ T cells contained stored MIP-1␤ that was released after HBa stimulation. Both HBa and LPS-Ba stimulated high levels of MIP-1␣ and MIP-1␤ production in elutriated monocytes and even higher levels in macrophages. In these cells, ␤-chemokine mRNA was upregulated within 30 min and proteins were secreted within 4 h of stimulation. The monocyte-and macrophage-derived ␤-chemokines were sufficient to block CCR5-dependent HIV-1 envelope-mediated cell fusion. These data suggest that, in addition to the ability of HBa to elicit antigen-specific humoral and cellular immune responses, HBa-conjugated HIV-1 proteins or peptides would also generate innate chemokines with antiviral activity that could limit local viral spread during vaccination in vivo.The discovery that several ␤-chemokines (i.e., macrophage inflammatory proteins 1␣ and 1␤ [MIP-1␣ and MIP-1␤, respectively] and RANTES) secreted by short-term human CD8 ϩ cell lines can effectively block infection of human peripheral blood mononuclear cells (PBMCs) with macrophage-

Notch and Wnt signaling in T-lymphocyte development and acute lymphoblastic leukemia

“…Transplantation of mice with progenitors overexpressing Delta1 or 4 phenocopied the effect of overexpression of IC-Notch: DP cells emerged in the BM. 37,38 In vitro, this phenomenon can be mimicked using BM-derived stromal cell lines (e.g. S17 or OP9) which otherwise promote myeloid and B-cell development of hematopoietic progenitor cells.…”

Notch/Delta4 signaling inhibits human megakaryocytic terminal differentiation

“…25 The stromal cells were plated 1 day before the start of coculture in 24-well plates at a density of 5 ϫ 10 4 cells/well. Human CD34 ϩ cells were plated onto the stromal cells in serum-free medium containing 5% FCS, huTPO (10 ng/mL), and huSCF (25 ng/mL), and cells were seeded onto fresh OP9 cells 5 days later before flow cytometric analysis.…”

Suppressor of Cytokine Signaling 3 Promotes Bone Marrow Cells to Differentiate into CD8+ T Lymphocytes in Lung Tissue via Up-Regulating Notch1 Expression

“…Indeed, others also reported that, in the absence of thymus, T-cell development from the most immature progenitor stages was developed into complete maturation of ah T cells (32). In vivo and in the absence of a thymus, y-1 or y-4 expression is sufficient to promote T-cell development from the most immature progenitor stages to complete maturation of both CD8 + and CD4 + T cells (32)(33)(34)(35). As a significant finding, we show that lung tissues, which express y-1 and y-4, can support differentiation of BMCs into CD8 + T cells.…”