Abstract
Human primary dendritic cells (DCs) are heterogeneous by phenotype, function, and tissue localization and distinct from inflammatory monocyte-derived DCs. Current information regarding the susceptibility and functional role of primary human DC subsets to Mycobacterium tuberculosis (Mtb) infection is limited. Here, we dissect the response of different primary DC subsets to Mtb infection. Myeloid CD11c+ cells and pDCs (C-type lectin 4C+ cells) were located in human lymph nodes (LNs) of tuberculosis (TB) patients by histochemistry. Rare CD141hi DCs (C-type lectin 9A+ cells) were also identified. Infection with live Mtb revealed a higher responsiveness of myeloid CD1c+ DCs compared to CD141hi DCs and pDCs. CD1c+ DCs produced interleukin (IL)-6, tumor necrosis factor α, and IL-1β but not IL-12p70, a cytokine important for Th1 activation and host defenses against Mtb. Yet, CD1c+ DCs were able to activate autologous naïve CD4+ T cells. By combining cell purification with fluorescence-activated cell sorting and gene expression profiling on rare cell populations, we detected in responding CD4+ T cells, genes related to effector-cytolytic functions and transcription factors associated with Th1, Th17, and Treg polarization, suggesting multifunctional properties in our experimental conditions. Finally, immunohistologic analyses revealed contact between CD11c+ cells and pDCs in LNs of TB patients and in vitro data suggest that cooperation between Mtb-infected CD1c+ DCs and pDCs favors stimulation of CD4+ T cells.
Highlights
Tuberculosis (TB) is caused by the intracellular bacterial pathogen Mycobacterium tuberculosis (Mtb)
CONTACT BETWEEN mDCs AND pDCs AND RELEASE OF granzyme B (GrB) BY pDCs IN lymph nodes (LNs) OF TB PATIENTS We previously described that pDCs help CD1c+ dendritic cells (DCs) in the control of Bacille Calmette–Guérin (BCG) infection and induction of mycobacteria-specific CD8 T cell response(s)
In contrast to BCG stimulation [10], low concentrations of IFNα were detected in culture of pDCs with Mtb-infected CD1c+ DCs (MOI 5, 48 h post-infection) (Figure 3A, blue diamonds, p < 0.05 compared to Mtb-infected CD1c+ DCs monocultures)
Summary
Tuberculosis (TB) is caused by the intracellular bacterial pathogen Mycobacterium tuberculosis (Mtb). Phagocytic cells such as macrophages engulf bacteria entering the lung and initiate a first line of defense, which controls Mtb growth and recruits pro-inflammatory cells [1]. Activation of the adaptive immune responses, notably T cells, occurs only at later time points after infection and involves the migration of infected dendritic cells (DCs) to the draining lymph nodes (LNs) [2,3,4]. The bacterial antigens presented in the LNs need to reach a critical abundance to efficiently activate a specific CD4+ T cell response [4]. Inhibition of DC maturation and trafficking and, suboptimal antigen presentation, likely contribute to delayed CD4+ T cell responses
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