Urban Particulate Matter Suppresses Priming of T Helper Type 1 Cells by Granulocyte/Macrophage Colony–Stimulating Factor–Activated Human Dendritic Cells

Abstract

Urban particulate matter (UPM) exacerbates asthmatic lung inflammation and depresses lung immunity. Lung dendritic cells (DCs) react to airway particulates, and have a critical role in linking innate and adaptive immunity, but the direct effects of UPM on DCs, that have been activated by granulocyte/macrophage colony-stimulating factor (GM-CSF), a product of stimulated normal human bronchial epithelial cells, has not been investigated. Human blood CD1c(+) DCs were purified and activated with UPM in the presence or absence of GM-CSF with and without LPS, and DC maturation was assessed by flow cytometry. DC stimulatory capacity and priming of 5-(and -6)-carboxyfluorescein diacetate succinimidyl ester-labeled naive CD4 T cells was investigated using the allogeneic mixed lymphocyte reaction. T cell proliferation and effector function were assessed using flow cytometry and secreted cytokines were measured by combined bead array. UPM enhanced DC maturation in an LPS-independent manner. DCs activated by UPM plus GM-CSF (UPM + GM-CSF DCs) induced higher naive CD4 T cell proliferation in the allogeneic mixed lymphocyte reaction than DCs pretreated by GM-CSF alone (GM-CSF DCs), and elicited both substantially lower levels of IFN-γ, IL-13, and IL-5 secretion, and lower frequencies of alloantigen-specific T helper (Th) type 1 effector cells than naive CD4 T cells primed by GM-CSF DCs. UPM-stimulated DCs produced IL-6 and TNF-α. Neutralization of IL-6 decreased naive CD4 T cell proliferation stimulated by UPM + GM-CSF DCs, and significantly increased the frequency of alloantigen-specific Th1 effector cells, but did not reverse UPM-induced inhibition of IFN-γ secretion. We conclude that UPM enhances GM-CSF-induced DC maturation and stimulatory capacity, but inhibits the generation of Th1 cells. Thus, UPM exposure may impair Th1 responses to pulmonary pathogens.

Urban particulate matter stimulation of human dendritic cells enhances priming of naive CD8 T lymphocytes

“…That such an effect is enhanced with GM‐CSF is in agreement with our current understanding for a pro‐inflammatory role for GM‐CSF in pollution‐induced lung disease 16, 18, 19. Although not the focus of this research, our finding of suppression of MHC class I expression by GM‐CSF is intriguing and deserves more detailed investigation in dedicated studies.…”

“…Possible mechanisms by which air pollution might impair anti‐microbial immune responses have been identified to explain this association 36, 37. Indeed our previous work with DC‐stimulated naïve CD4 T lymphocytes showed decreased priming of IFN γ ‐producing CD4 T lymphocytes in similar experiments examining the effect of adding UPM to GM‐CSF‐treated mDCs 16. However, the present research with naive CD8 T lymphocytes, using a comparable experimental system, does not show UPM to impair priming of an IFN‐ γ ‐producing CD8 response, but in contrast demonstrates enhancement of this response.…”

Urban Particulate Matter–Activated Human Dendritic Cells Induce the Expansion of Potent Inflammatory Th1, Th2, and Th17 Effector Cells

“…To test the hypothesis that UPM stimulation of DCs (UPM-DCs) enhances T cell recall responses to allergen, Tms from patients with asthma with allergy to HDM were cocultured with autologous DCs pretreated overnight in the presence or absence of a fixed dose of UPM (previously optimized at 5 mg/ml [23]) with or without HDM (dose range 0-500 standardizedquality [SQ] units/ml). Cells were cultured for 5 days and IL-13 secretion in supernatants was measured by CBA.…”

“…We previously established that UPM directly matures human CD1c 1 myeloid DCs, which are the precursors of DCs that populate the lung mucosa and submucosa, and enhance the maturation induced by granulocyte/ macrophage colony-stimulating factor (GM-CSF), a product of UPM-stimulated AECs, that is essential for lung myeloid DC survival and differentiation (21,22). We found that UPM-activated DCs are capable of priming alloantigen-specific human naive CD4 T cell proliferation, but suppress the capacity of newly primed cells to produce Th1 and Th2 cytokines (23).…”

The Value of Extracorporeal Photochemotherapy in Renal Transplant Rejection Inhibition

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