Analysis of transcription factors in thymic and CD34+ progenitor-derived plasmacytoid and myeloid dendritic cells: evidence for distinct expression profiles.

OBJECTIVE: The expression of mRNA for pre-Talpha is specific for human plasmacytoid dendritic cells (PDC), a population ontogenically close to T cells. The latter need Gata-3 transcription factor to develop. PU1 and RelB are two transcription factors involved in the development of murine myeloid DC (MDC). To determine the lineage origin of human thymic DC, the expression of these genes was investigated. MATERIALS AND METHODS: Fresh thymic DC, CD34(+)CD1a(-) progenitors, and progenitor-derived DC populations were sorted, analyzed, and compared to blood DC. RESULTS: Three DC populations were found in the thymus. 1) CD123(-/lo)HLA-DR(hi) DC expressing PU1 and RelB; 2) CD123(hi)HLA-DR(+) DC expressing only pre-Talpha, the expression of which was similar to that of MDC and PDC from peripheral blood; and 3) a new mature CD123(hi)HLA-DR(hi) PDC population with pre-Talpha, PU1 and RelB mRNAs. In culture, most CD34(+)CD1a(-) progenitors remained CD1a(-)CD123(-); had a T and natural killer cell differentiation potential; and expressed Gata-3 mRNA contrary to DC precursors. A few cells (10%) became CD1a(+)CD123(+) expressing pre-Talpha, PU1, and RelB mRNAs and were able to differentiate into typical Langerhans cells with transforming growth factor-beta. Coculture of thymic progenitors on a murine cell line generated CD123(hi)CD1a(-) cells with typical PDC morphology, expressing pre-Talpha but not PU1 and RelB transcripts. Activated PDC acquired myeloid antigens, and up-regulated PU1 and RelB mRNAs while down-regulating pre-Talpha mRNA expression. CONCLUSION: Both DC maturation pathways may arise from distinct precursors but are interconnected. DC differentiation seems to occur from Gata-3(-) precursors upstream of T and natural killer precursors.

Type I interferon production by plasmacytoid dendritic cells and monocytes is triggered by viruses, but the level of production is controlled by distinct cytokines.

The principal interferon-alpha/beta (IFN-I)-producing cells are plasmacytoid dendritic cell (PDC) precursors belonging to the lymphoid lineage. Monocytes that can differentiate into dendritic cells (DC) also produce IFN-I, although much less than PDC, after interaction with infectious agents. We show that whereas viruses trigger these cells to produce IFN-I, the amount of IFN is tightly controlled by cytokines. Monocytes produced IFN-I in response to Sendai virus (SV) infection, and PDC responded to both SV and herpes simplex virus (HSV). All cytokines tested failed to induce production of IFN-I in the absence of infection. However, among 18 relevant cytokines, incubation of PDC with interleukin-4 (IL-4), IL-15, and IL-7 alone or in combination with IL-3 before infection, enhanced IFN-I secretion. At variance, IL-12 alone or in synergy with granulocyte-macrophage colony-stimulating factor (GM-CSF) was active on SV-infected but not on HSV-infected monocytes. Tumor necrosis factor-alpha (TNF-alpha) and IL-4 inhibited IFN-I production by PDC and monocytes, respectively, and IL-10 strongly inhibited IFN-I production in both cell lineages. The response of PDC to IL-7 and IL-15, which also activate natural killer (NK) cell maturation, further emphasizes the cooperation between these two cell subsets in the control of innate immunity.

Human CD5 promotes B-cell survival through stimulation of autocrine IL-10 production.

CD5 is a negative regulator of B-cell receptor (BCR) signaling that is up-regulated after BCR stimulation and likely contributes to B-cell tolerance in vivo. However, CD5 is constitutively expressed on the B-1 subset of B cells. Contrary to CD5(-) B-2 B cells, B-1 B cells are long-lived because of autocrine interleukin-10 (IL-10) production through unknown mechanisms. We demonstrate herein a direct relationship between CD5 expression and IL-10 production. Human peripheral blood CD5(+) B cells produce more IL-10 than CD5(-) B cells after BCR activation. Introducing CD5 into CD5(-) B cells induces the production of IL-10 by activating its promoter and the synthesis of its mRNA. The cytoplasmic domain of CD5 is sufficient for this process. CD5 also protects normal human B cells from apoptosis after BCR stimulation while reducing the BCR-induced Ca(2+) response. We conclude that CD5 supports the survival of B cells by stimulating IL-10 production and by concurrently exerting negative feedback on BCR-induced signaling events that can promote cell death.