It has been almost a decade since the Lung Health Study shed light on a critical aspect of smoking-related lung disease that had not yet been appreciated: over time, approximately 40% of active smokers develop significant obstructive lung physiology, and, despite smoking cessation, another 10% also develop lung disease (1). This revelation should not have caused an enormous surprise because for years pathologists had described how large numbers of innate and adaptive immune cells are embedded within the lung tissue of former smokers with chronic obstructive pulmonary disease (COPD) and emphysema (2). Together, however, these intriguing clinical and pathological observations opened the door to a new concept: in susceptible individuals, cigarette-smoke exposure could trigger long-lasting inflammatory memory responses that persist beyond the immediate period of exposure to cigarette smoke. Whereas human and experimental studies have provided unequivocal evidence for the ability of cigarette smoke to activate innate immune cells, such as neutrophils and macrophages, in the airway, new findings are now emerging that support a critical role for adaptive immunity (ie, T and B cells) and antigen recall long after smoke exposure has ceased (3). In search of factors that might operate as breaks or accelerators of inflammation, the focus is now on critical cells that can educate lymphocytes and, specifically, lead to durable immunological memory. As expected, immune cells operate according to a specific hierarchy in their mission to ward off infection or keep rogue cells in check. In particular, newly minted T lymphocytes, including CD4 and CD8 T cells, emerge from the thymus, enter the blood circulation, and make their journey through various tissues, with their final assignations determined specifically by antigen presenting cells (APCs).

A major type of dedicated (ie,‘‘professional’’) APC is known as the dendritic cell (DC), which includes myeloid DC (mDC) and plasmacytoid (pDC) subtypes (4). The eponymous long, protruding dendritic processes of mDCs endow them with the unique capacity to sample antigens in the airway via DEC205 (CD205) and macrophage mannose receptors (MMR) and other cell surface molecules that mediate receptor-mediated endocytosis and antigen processing in deep lysosomes or peripheral endosomes, respectively (5). The digested foreign-or selfpeptides are then displayed together with major histocompatibility (MHC) molecules, and only then is antigen capable of being recognized by lymphocytes. For years, the nature of the elusive lung DC was poorly understood, but with increasing interest in the role of adaptive immunity in the pathophysiology of human COPD and emphysema, interest in further characterizing specific DC subsets in normal and diseased lung arose. A DC is termed mature if it is no longer capable of sampling antigen in the environment but has increased expression of accessory T cell stimulatory molecules, called costimulatory molecules, that aid in the activation of antigen-specific lymphocytes (6). Thus, mature DCs with a mission to educate lymphocytes come dressed for the occasion: they express not only MHC molecules complexed with peptides, but also costimulatory molecules (CD80, CD86, CD83, CD40) to optimally activate T cells (7). How DCs undergo this unique maturation process remains an intense area of investigation. Specifically, although much is known