CD40 Ligation on Human Cord Blood CD34+Hematopoietic Progenitors Induces Their Proliferation and Differentiation into Functional Dendritic Cells

Abstract

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.

IL-4 and CD40 ligation affect differently the differentiation, maturation, and function of human CD34+ cell-derived CD1a+CD14− and CD1a−CD14+ dendritic cell precursors in vitro

“…These results are in line with reports on the effect of IL-4 [13,14,16,17,[34][35][36][37][38] and CD40 ligation [22,23,32] on DC differentiation from CD34 ϩ HPC as well as from monocytes or skin LC. They confirm the previously reported ontological dichotomy between DC and LC [3,5], and demonstrate that not only IL-4, but also CD40 ligation can prevent differentiation of bipotent CD1a Ϫ CD14 ϩ precursors into macrophages [32].…”

“…It is interesting to note that DC differentiated in the presence of only GM-CSF and TNF-␣ remained RelB lo/-, suggesting that this factor mainly acts by transducing activation or survival signals [31][32][33], although one cannot exclude that only low nuclear levels of RelB can trigger DC differentiation from their precursors. In spite of these similarities, DC differentiated from both precursors retained several original features in relationship with their origin: S100 was preferentially expressed by DC derived from CD1a ϩ CD14 Ϫ precursors, whereas DC generated from CD1a Ϫ CD14 ϩ precursors stayed CD11b ϩ on CD40 ligation [34].…”

Interferon-α and granulocyte-macrophage colony-stimulating factor differentiate peripheral blood monocytes into potent antigen-presenting cells

“…The addition of anti-TNF-␣ antibodies to cultures containing IFN-␣ and GM-CSF did not affect the generation of DCs. More recently, ligation of CD40 on CD34 ϩ hematopoietic progenitor cells was shown to induce them to differentiate into DCs [62]. Flow cytometry for CD40 ligand was performed on the lymphocyte population of the DC cultures in order to exclude the possibility that IFN-␣ induction of CD40 ligand expression on T cells was indirectly responsible for DC differentiation; no CD40 ligand expression was observed.…”

Early reduction of the over-expression of CD40L, OX40 and Fas on T cells in HIV-1 infection during triple anti-retroviral therapy: possible implications for lymphocyte traffic and functional recovery

“…Fas (CD95, APO-1)/Fas ligand is a key cellular apoptotic pathway involved in the physiologic regulation of immune responses [18], which has Clin Exp Immunol 1999; 116:307-315 been proposed to play a role in HIV-associated lymphocyte anergy and programmed cell death [19]. On the other hand, CD40L (CD154 or gp39) and OX40 (CD134) are molecules transiently expressed on the surface of T cells upon activation with fundamental roles on T-B cell interactions [20,21], as well as important effects on T cell differentiation [22] and on dendritic cell maturation [23,24]. Furthermore, they promote endothelial cell activation and expression of adhesion molecules that contribute to regulate leucocyte traffic and inflammatory responses [25,26].…”