Dendritic Cells of Vital Importance for Immune Regulation in the Lung for Immune Regulation in the Lung

Dendritic cells (DCs) are known to play a pivotal role in the induction of a primary and secondary immune response in the lung (1) (see chapter 2 for a full theoretical introduction on DC subsets). By taking up antigen under steady state and inflammatory conditions from the tissue where they reside, DCs can subsequently migrating to draining lymph nodes (LNs). Here they can present antigen bound peptides on either MHC class I and/or II to CD8+ or CD4+ T cells respectively. These DCs induce either tolerance or immunity, depending on the type of stimulus that they received during residence in the periphery (2). Recently it has become clear that there are different subtypes of DCs, with a major division between conventional DC (cDC), plasmacytoid DC (pDC), and an inflammatory type DC (iDC). The cDC is found in steady state conditions in the central lymphoid organs and some peripheral tissues like lung, gut and skin. The pDC was known to be a major interferon producing cell type, but later on also proved to have antigen presenting cell (APC) qualities under certain conditions. The iDCs derive from monocytes under conditions of inflammation and can be generated in large quantities from human monocytes, and mouse bone marrow cells (3). Although this emerging concept of DC subsets is now well accepted for central lymphoid organs and skin, relatively little is known about the precise control mechanisms of lung DC function and possible regulation by different DC subsets. Studying the precise regulation of DC function on the lung could however be key to understanding many immune mediated diseases of the lung such as asthma, sarcoidosis, hypersensitivity pneumonitis or other interstitial diseases of unknown origin. In this thesis, we specially addressed the functional contribution of different DC subsets, the importance of their maturation state and type of innate stimulation on the regulation of the pulmonary immune response, and how this can influence the decision between tolerance or immunity, health or disease. Furthermore the role of these DC subsets was investigated in two important anatomical compartments of the lung namely the conducting airways and the peripheral vascular compartment. The importance of the degree of maturity of iDCs was studied, attempting to modulate DC functions using a Toll-like receptor (TLR) agonist in vitro, or anti-inflammatory compounds.

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