Infection Rate and Tissue Localization of Murine IL-12p40-Producing Monocyte-Derived CD103+ Lung Dendritic Cells during Pulmonary Tuberculosis

Abstract

Non-hematopoietic cells, including lung epithelial cells, influence host immune responses. By co-culturing primary alveolar epithelial cells and monocytes from naïve donor mice, we show that alveolar epithelial cells support monocyte survival and differentiation in vitro, suggesting a role for non-hematopoietic cells in monocyte differentiation during the steady state in vivo. CD103+ dendritic cells (αE-DC) are present at mucosal surfaces. Using a murine primary monocyte adoptive transfer model, we demonstrate that αE-DC in the lungs and pulmonary lymph nodes are monocyte-derived during pulmonary tuberculosis. The tissue localization may influence the functional potential of αE-DC that accumulate in Mycobacterium tuberculosis-infected lungs. Here, we confirm the localization of αE-DC in uninfected mice beneath the bronchial epithelial cell layer and near the vascular wall, and show that αE-DC have a similar distribution in the lungs during pulmonary tuberculosis and are detected in the bronchoalveolar lavage fluid from infected mice. Lung DC can be targeted by M. tuberculosis in vivo and play a role in bacterial dissemination to the draining lymph node. In contrast to other DC subsets, only a fraction of lung αE-DC are infected with the bacterium. We also show that virulent M. tuberculosis does not significantly alter cell surface expression levels of MHC class II on infected cells in vivo and that αE-DC contain the highest frequency of IL-12p40+ cells among the myeloid cell subsets in infected lungs. Our results support a model in which inflammatory monocytes are recruited into the M. tuberculosis-infected lung tissue and, depending on which non-hematopoietic cells they interact with, differentiate along different paths to give rise to multiple monocyte-derived cells, including DC with a distinctive αE-DC phenotype.

Hyperoxic Exposure of Immature Mice Increases the Inflammatory Response to Subsequent Rhinovirus Infection: Association with Danger Signals

“…Mouse lung DCs contain two major subpopulations: CD103+ CD11b low (or CD11b-negative) DCs and CD103-negative CD11b high DCs (41–43). CD103+ DCs produce IL-12 and IFN-γ (44–46) and predominantly elicit Th1 and Th17 responses (47), whereas CD11b high DCs primarily provoke a Th2 response (47, 48). We found that hyperoxic exposure was associated with an increase in lung CD103+, MHCII hi , CD86 hi DCs, a population of cells which was further increased upon viral infection.…”

The crucial roles of Th17-related cytokines/signal pathways in M. tuberculosis infection

“…[47][48][49] In vivo, the expression of IL-23α is enhanced in PBMCs in nonhuman primates at the early stage of mycobacteria infection; later, its expression decreases to the normal level. 50 Moreover, levels of IL-12p40, one subunit of IL-23, are higher in the serum of TB patients than in HCs and decrease after anti-TB treatments. 48,50 IL-23 could mediate its effects on both innate and adaptive arms of the immune system that express the IL-23R.…”

“…50 Moreover, levels of IL-12p40, one subunit of IL-23, are higher in the serum of TB patients than in HCs and decrease after anti-TB treatments. 48,50 IL-23 could mediate its effects on both innate and adaptive arms of the immune system that express the IL-23R. 48 Th17 cells are the representative T-cell subset that vigorously responds to IL-23.…”

Innate and Adaptive Cellular Immune Responses toMycobacterium tuberculosisInfection

“…þ DCs are present exclusively in the lung airways and parenchyma after Mtb infection and are considered lung resident DCs, with migratory capacity to the draining lymph node (GeurtsvanKessel et al 2008;Geissmann et al 2010;Guilliams et al 2013b;Leepiyasakulchai et al 2013;Anderson et al 2014). cDCs and CD103 þ cDCs represent a functionally and phenotypically distinct pulmonary DC subset after Mtb infection and produce predominantly IL-12/ 23p40 (Mayer- Barber et al 2011;Leepiyasakulchai et al 2013).…”

“…cDCs and CD103 þ cDCs represent a functionally and phenotypically distinct pulmonary DC subset after Mtb infection and produce predominantly IL-12/ 23p40 (Mayer- Barber et al 2011;Leepiyasakulchai et al 2013). They express all the classical DC surface molecules (high levels of major histocompatibility complex class II (MHC-II), CD80, and CD86) as well as additional markers associated with antigen presentation and antigen-presenting cell (APC)-T-cell interactions, such as CD40, CD70, DEC-205, CD83, and PD-L2 (Mayer- Barber et al 2011;KD MayerBarber, unpubl.…”