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C Caux

Publications and source records attributed to C Caux.

At least 55 records · Page 3Linked to original sources
PubMed1996

CD34+ hematopoietic progenitors from human cord blood differentiate along two independent dendritic cell pathways in response to GM-CSF+TNF alpha.

Human dendritic cells (DC) can now be generated in vitro in large numbers by culturing CD34+ hematopoietic progenitors in presence of GM-CSF+TNF alpha for 12 d. The present study demonstrates that cord blood CD34+ HPC indeed differentiate along two independent DC pathways. At early time points (day 5-7) during the culture, two subsets of DC precursors identified by the exclusive expression of CD1a and CD14 emerge independently. Both precursor subsets mature at day 12-14 into DC with typical morphology and phenotype (CD80, CD83, CD86, CD58, high HLA class II). CD1a+ precursors give rise to cells characterized by the expression of Birbeck granules, the Lag antigen and E-cadherin, three markers specifically expressed on Langerhans cells in the epidermis. In contrast, the CD14+ progenitors mature into CD1a+ DC lacking Birbeck granules, E-cadherin, and Lag antigen but expressing CD2, CD9, CD68, and the coagulation factor XIIIa described in dermal dendritic cells. The two mature DC were equally potent in stimulating allogeneic CD45RA+ naive T cells. Interestingly, the CD14+ precursors, but not the CD1a+ precursors, represent bipotent cells that can be induced to differentiate, in response to M-CSF, into macrophage-like cells, lacking accessory function for T cells. Altogether, these results demonstrate that different pathways of DC development exist: the Langerhans cells and the CD14(+)-derived DC related to dermal DC or circulating blood DC. The physiological relevance of these two pathways of DC development is discussed with regard to their potential in vivo counterparts.

Antigens, CD1↗
PubMed1996

Interleukin-3 cooperates with tumor necrosis factor alpha for the development of human dendritic/Langerhans cells from cord blood CD34+ hematopoietic progenitor cells.

We have previously shown that tumor necrosis factor (TNF)alpha strongly potentiates the granulocyte-macrophage colony-stimulating factor (GM-CSF)/interleukin (IL)-3-dependent proliferation of CD34+ hematopoietic progenitor cells (HPC) through the recruitment of early progenitors with high proliferative potential. Furthermore, the combination of GM-CSF and TNFalpha allows the generation of large numbers of dendritic/Langerhans cells (D-Lc). Herein, we analyzed whether IL-3, when combined to TNFalpha would, as does GM-CSF, allow the generation of CD1a+ D-Lc. Accordingly, cultures of cord blood CD34+ HPC with IL-3 + TNFalpha yielded 20% to 60% CD14+ cells and 11% to 17% CD1a+ cells, while IL-3 alone did not generate significant numbers of CD1a+ cells. Although the percentage of CD1a+ cells detected in IL3 + TNFalpha was lower than that observed in GM-CSF + TNFalpha (42% to 78%), the strong growth induced by IL-3 + TNFalpha generated as many CD1a+ cells as did GM-CSF + TNFalpha. The CD14+ and CD1a+ cells generated with IL-3 + TNFalpha are similar to CD14+ and CD1a+ cells generated in GM-CSF alone and GM-CSF + TNFalpha, respectively. CD1a+ cells differed from CD14+ cells by (1) dendritic morphology, (2) higher expression of CD1a, CD1c, CD4, CD40, adhesion molecules (CD11c, CD54, CD58), major histocompatibility complex (MHC) class II molecules and CD28 ligands (CD80 and CD86), (3) lack of Fc receptor FcgammaRI (CD64) and complement receptor CR1 (CD35) expression, and (4) stronger induction of allogeneic T-cell proliferation. Thus, in combination with TNFalpha, IL-3 is as potent as GM-CSF for the generation of CD1a+ D-Lc from cord blood CD34+ HPC. The dendritic cell inducing ability of IL-3 may explain why mice with inactivated GM-CSF gene display dendritic cells.

Adult↗
PubMed1995

Human dendritic Langerhans cells generated in vitro from CD34+ progenitors can prime naive CD4+ T cells and process soluble antigen.

Earlier studies have concluded that fresh Langerhans cells (LC) are able to capture and process native Ags, whereas cultured LC have lost these functions while acquiring the capacity to prime naive T cells. Herein we studied the functions of human dendritic/Langerhans cells (d-Lc) generated in vitro by culturing CD34+ hemopoietic progenitor cells in the presence of granulocyte-macrophage CSF (GM-CSF) + TNF-alpha. Less than 50 d-Lc were found to strongly stimulate the proliferation of 2.5 x 10(4) allogeneic naive CD4+ T cells. Furthermore, six to 50 d-Lc induced half-maximal proliferation of naive syngeneic CD4+ cord blood T cells, in the presence of picomolar concentrations of superantigens. During the alloreaction, the CD4+ T cells were expanded up to 100-fold within two successive stimulation cycles with the same d-Lc, and the recovered T cells were specific for the d-Lc alloantigen. HLA-matched tetanus toxoid (TT)-specific T cell clones were found to proliferate in response to TT presented by CD1a+ d-Lc. Finally, electron microscopy demonstrated that CD1a+ d-Lc were able to capture an Ag (gold-labeled Igs) through receptor-mediated endocytosis. Thus, in vitro generated d-Lc can prime naive T cells and process native Ags, a property that might eventually prove useful for priming Ag-specific naive T cells for cellular immunotherapy.

Adult↗
PubMed1995

Abnormalities of lymphocyte subsets in canine systemic lupus erythematosus.

Canine systemic lupus erythematosus (SLE) is a disease clinically very similar to its human counterpart. But so far, no study has reported an accurate evaluation of the lymphocyte subsets in the canine disease. Here, we present a study in which lymphocyte subsets have been evaluated in the peripheral blood of 20 dogs suffering from spontaneous systemic lupus erythematosus (SLE) in active and inactive phases, before and during treatment with prednisone and levamisole. 22 healthy dogs have been used as a control population. We show that canine SLE in active phases is associated with a several lymphopenia (1050 +/- 520 10(6) cells/l versus 2130 +/- 1 020 10(6) cells/l in controls). A striking finding is the imbalance of the CD4 and CD8 subsets (respectively 56.7 +/- 10.7% and 10.9 +/- 3.8% of CD4+ and CD8+ lymphocytes versus 40.5 +/- 11.5% and 18 +/- 4.4% in controls) and a strong activation of T-cells in active phases (64.1 +/- 16.9% of 2B3+ cells versus 46.5 +/- 16.7%). Moreover, we observed a persistence of the T subset imbalance during spontaneous evolution. In contrast, the treatment induced in dogs showing a good response the correction of CD4/CD8 ratio and no clinical manifestations, whereas in low responders no such improvements were observed. Thus, this work suggests that the main immunological imbalance seen in SLE could be associated with defective suppressor cells and provides further evidence of similarity of human and dog SLE.

Animals↗
PubMed1995

[In vitro differenciation and functions of dendritic cells obtained from CD34+ hematopoietic progenitors].

Dendritic Cells (DC) are professional antigen presenting cells, necessary during the initiation of immune responses. The study of the role of DC in the establishment of this response has long been tempered by the difficulties to purify DC in sufficient numbers. In vitro generation of DC, from CD34+ hematopoietic progenitors in human and mice, should permit to clarify the relationships between the different DC types isolated in vivo and their roles. GM-CSF has been described to play a key role in the propagation of DC. In human, in association with TNF alpha, it allows the generation of DC from CD34+ progenitors. Those in vitro generated DC are capable of receptor mediated endocytosis and can present soluble antigen to specific T cell clones and activate naive T cells. During activation of naive T cells CD86 (on DC)--CD28 (on T lymphocyte) interaction seems to play a critical role. Interestingly, DC express a functional CD40, which triggering upregulates expression of CD80 and CD86 and induces cytokine production, indicating a reciprocal talk between DC and T cells during the course of antigen presentation. Finally, in vitro generated DC interact directly with B cells, activated through their CD40 antigen, leading to enhanced growth, differentiation (IgM production) and preferential isotype switch towards IgA. Thus, in the extrafollicular area of secondary lymphoid organs, in addition to prime naive T cells, DC might also directly provide costimulatory signals involved during the initiation of primary B cell responses.

Animals↗
PubMed1994

B70/B7-2 is identical to CD86 and is the major functional ligand for CD28 expressed on human dendritic cells.

Dendritic cells comprise a system of highly efficient antigen-presenting cells involved in the initiation of T cell responses. Herein, we investigated the role of the CD28 pathway during alloreactive T cell proliferation induced by dendritic-Langerhans cells (D-Lc) generated by culturing human cord blood CD34+ progenitor cells with granulocyte/macrophage colony-stimulating factor and tumor necrosis factor alpha. In addition to expressing CD80 (B7/BB1), a subset of D-Lc expressed B70/B7-2. Binding of the CTLA4-Ig fusion protein was completely inhibited by a combination of monoclonal antibodies (mAbs) against CD80 and B70/B7-2, indicating the absence of expression of a third ligand for CD28/CTLA-4. It is interesting to note that mAbs against CD86 completely prevented the binding of CTLA4-Ig in the presence of mAbs against CD80 and bound to a B70/B7-2-transfected fibroblast cell line, demonstrating that the B70/B7-2 antigen is identical to CD86. CD28 triggering was essential during D-Lc-induced alloreaction as it was inhibited by mAbs against CD28 (9 out of 11 tested). However, none of six anti-CD80 mAbs demonstrated any activity on the D-Lc-induced alloreaction, though some were previously described as inhibitory in assays using CD80-transfected cell lines. In contrast, a mAb against CD86 (IT-2) was found to suppress the D-Lc-dependent alloreaction by 70%. This inhibitory effect was enhanced to > or = 90% when a combination of anti-CD80 and anti-CD86 mAbs was used. The present results demonstrate that D-Lc express, in addition to CD80, the other ligand for CTLA-4, CD86 (B70/B7-2), which plays a primordial role during D-Lc-induced alloreaction.

Abatacept↗
PubMed1994

Activation of human dendritic cells through CD40 cross-linking.

Dendritic cells, the professional antigen-presenting cells (APC) involved in T cell priming, express CD40, a molecule which triggering plays a key role in B cell growth and differentiation as well as monocyte activation. Herein we demonstrate that dendritic Langerhans cells (D-Lc) generated by culturing cord blood CD34+ progenitor cells with granulocyte/macrophage colony-stimulating and tumor necrosis factor alpha (TNF-alpha) express functional CD40 at a density higher than that found on B cells. Culturing D-Lc on CD40-ligand (CD40L) transfected L cells allowed D-Lc survival as 50 +/- 15% of seeded cells were recovered after 4 d while only 5% survived over control L cells. CD40 activation induced important morphological changes with a reduction of cytoplasmic content and a remarkable increase of dendrite development as well as an altered phenotype. In particular, CD40 triggering induced maintenance of high levels of major histocompatibility complex class II antigens and upregulation of accessory molecules such as CD58, CD80 (B7-1) and CD86 (B7-2). CD40 engagement also seems to turn on D-Lc maturation as illustrated by upregulation of CD25, a molecule usually expressed on interdigitating dendritic cells of secondary lymphoid organs. Finally, CD40 activated D-Lc secreted a limited set of cytokines (TNF-alpha, IL-8, and macrophage inflammatory protein 1 alpha [MIP-1 alpha]) whereas a similar activation induced elutriated monocytes to secrete IL-1 alpha, IL-1 beta, IL-6, IL-8, IL-10, TNF-alpha, and MIP-1 alpha. As D-Lc activated T cells upregulated CD40L, it is likely that CD40 activation of D-Lc observed herein with a fibroblast cell line stably expressing CD40L, mimics physiological interactions between dendritic cells and T cells.

Adult↗
PubMed1994

Interleukin-10 inhibits the primary allogeneic T cell response to human epidermal Langerhans cells.

In this study, we analyzed the effect of interleukin-10 (IL-10) on the primary allogeneic T cell response induced by human Langerhans cells (LC), the dendritic cells from epidermis. We showed that IL-10 strongly inhibited the T cell response, provided it was added at the beginning of the mixed epidermal cell lymphocyte reaction (MELR). Proliferation of both CD4+ and CD8+ T cell subsets was affected by the cytokine. An inhibitory effect of IL-10 on human LC allostimulatory function was evidenced by the fact that IL-10-preincubated LC, but not IL-10-preincubated T cells, can display inhibitory effect. LC treatment with IL-10 partially inhibited the increase of HLA-DR expression on cultured LC as the percentage of highly positive HLA-DR cells was lower than that observed in the absence of the cytokine. IL-10 inhibited T cell alloreaction induced by 2-day-cultured human LC which constitutively display high levels of HLA class II, as well as ICAM-1 and LFA-3 antigens. This suggests that the suppressive effect of the cytokine was not merely related to an impaired up-regulation of these molecules. Addition of IL-1 during the MELR potentiated the allogeneic T cell proliferation and could reverse, at least partly, the inhibitory effect of IL-10. Collectively, these data indicate that IL-10 can prevent the alloreaction induced by human dendritic cells, providing new insights into the potential clinical use of this cytokine.

Cells, Cultured↗