No abstract

Dendritic cells (DC) are cells of the hematopoletic system specialized in capturing antigens and initiating T cell-mediated immune responses. We show here that human DC generated in vitro by culturing CD34+ cord blood progenitor cells in granulocyte macrophage colony stimulating factor plus tumor necrosis factor-alpha express the Fas antigen (APO-1, CD95) and undergo apoptosis upon triggering of Fas by mAb. However, only a proportion of the cells die in response to Fas ligation, an observation that may be related to the virtual absence of the bcl-2 protein in about half of the cells. Ligation of DC CD40 by culture on CD40L-transfected fibroblastic cells up-regulates the expression of bcl-2 and, concomitantly, renders DC virtually resistant to Fas-induced apoptosis. Parallel experiments with mature, interdigitating dendritic cells (IDC) isolated from tonsils revealed that IDC express Fas but do not enter into apoptosis following Fas ligation, a finding that may be explained by their high levels of bcl-2. Thus, upon encountering antigen-specific T cells, DC become resistant to Fas-induced apoptosis, as a consequence of CD40 ligation and possibly by mechanisms associated to the up-regulation of bcl-2 protein expression.

Plasmacytoid dendritic cells (pDC) produce large amounts of type I interferon in response to invading pathogens, but can also suppress immune responses and promote tolerance. Here we show that in mice these functions are attributable to two distinct pDC subsets, one of which gives rise to the other. CD9pos Siglec-Hlow pDC secrete interferon-α (IFN-α) when stimulated with Toll-like receptor (TLR) agonists, induce cytotoxic T lymphocytes (CTLs) and promote protective anti-tumor immunity. By contrast, CD9neg Siglec-Hhigh pDC secrete negligible amounts of IFN-α, induce FoxP3+ CD4+ T cells and fail to promote anti-tumor immunity. Although newly formed pDC in the bone marrow (BM) are CD9pos and are capable of producing IFN-α, after these cells traffic to peripheral tissues they lose CD9 expression and the ability to produce IFN-α. We propose that newly generated pDC mobilized from the BM, rather than tissue-resident pDC, are the major source of IFN-α in infected hosts.

Human CD34+ multilineage progenitor cells (CD34HPC) from cord blood and bone marrow express CD40, a member of the tumor necrosis factor–receptor family present on various hematopoietic and nonhematopoietic cells. As hyper-IgM patients with mutated CD40 ligand (CD40L) exhibit neutropenia, no B cell memory, and altered T cell functions leading to severe infections, we investigated the potential role of CD40 on CD34HPC development. CD40activated cord blood CD34HPC were found to proliferate and differentiate independently of granulocyte/macrophage colony-stimulating factor, into a cell population with prominent dendritic cell (DC) attributes including priming of allogeneic naive T cells. DC generated via the CD40 pathway displayed strong major histocompatibility complex class II DR but lacked detectable CD1a and CD40 expression. These features were shared by a dendritic population identified in situ in tonsillar T cell areas. Taken together, the present data demonstrate that CD40 is functional on CD34HPC and its cross-linking by CD40L+ cells results in the generation of DC that may prime immune reactions during antigen-driven responses to pathogenic invasion, thus providing a link between hematopoiesis, innate, and adaptive immunity.