Several new studies that utilize models of asthma relate to lung transplantation. A new avenue in the prevention of chronic lung rejection could utilize methods that toggle lung mononuclear cells toward a phenotype that induces regulatory T cells. Several new studies that utilize models of asthma relate to lung transplantation. A new avenue in the prevention of chronic lung rejection could utilize methods that toggle lung mononuclear cells toward a phenotype that induces regulatory T cells. Lung Macrophages Influence Regulatory T Cells in Asthma Models CITATION Coleman MM, Ruane D, Moran B, Dunne PJ, Keane J, Mills KH. Alveolar macrophages contribute to respiratory tolerance by inducing FoxP3 expression in naive T cells. Am J Respir Cell Mol Biol 2013; 48: 773-780. CITATION Soroosh P, Doherty TA, Duan W, Mehta AK, Choi H, Adams YF, et al. Lung-resident tissue macrophages generate Foxp3+ regulatory T cells and promote airway tolerance. J Exp Med 2013; 210: 775-788. An extensive body of research has focused on the pathogenesis of airway inflammatory disorders such as asthma and bronchitis. Because the respiratory tract exists in a state of continuous exposure to the environment, many have asked why the prevalence of airway disorders is not higher. It has been increasingly recognized that active processes exist to dampen the underlying immune activation state. Two recent studies have focused on interactions between macrophages and induction of regulatory T cells. To understand these recent findings it is important to understand the distinct subpopulations of antigen-presenting cells present within the lung. Alveolar macrophages reside in the alveolus, are thought to be derived from a population of monocytes that have traversed through the lung into the alveolus and are involved primarily in phagocytosis of inhaled materials. Lung resident macrophages reside within the interstitium, the anatomic compartment found between the vasculature and the airspaces. Studies in mice have shown that bone marrow-derived monocytes migrate into the lung to generate the alveolar macrophage compartment, having transitioned through the interstitium. Finally, at least two distinct categories of dendritic cells, classical dendritic cells (cDCs) and plasmacytoid dendritic cells (pDCs), have been described that in some cases can dampen immune responses. Soroosh et al examined how tissue resident macrophages imbue naive T cells with a regulatory phenotype (Treg). In their model murine lungs were first lavaged free of alveolar macrophages. They identified a population of mononuclear tissue resident macrophages based on autofluorescence and a panel of cell surface markers including F4/80, Siglec F and CD68. They performed co-culture experiments with T cell receptor transgenic CD4+ T cells specific for the ovalbumin (OVA) peptide. The lung resident macrophages, but not the cDCs, induced significant expression of the suppressive transcription factor Foxp3 in the CD4 cells, indicating that the tissue resident macrophages could induce nonregulatory T cells to become Tregs. The investigators applied these findings to the murine OVA asthma model. Tissue resident macrophages were pulsed with OVA and instilled into the trachea of mice. These mice were subsequently challenged with OVA plus adjuvant. Pretreatment with the pulsed tissue resident macrophages dramatically reduced airway inflammation, eosinophilia and airway resistance (see Figure 1). In contrast to tissue resident macrophages, Coleman et al have interrogated the ability of alveolar macrophages from mice and humans to dampen immune responses. They utilized bronchoalveolar lavage cells and showed that alveolar macrophages or the conditioned media from these cells were able to induce Foxp3 expression in both naive and memory phenotype CD4 T cells. They found that the combined effect of transforming growth factor β and retinoic acid were responsible for this effect. Hence, when mice were challenged with nasal OVA and treated with an inhibitor to retinoic acid, the frequency of lung Foxp3+ cells decreased. In contrast to the studies of tissue resident macrophages, alveolar macrophages did not require pretreatment with OVA to exert their effect. This could be due to the relatively high frequency of these cells in the airway at baseline, or intrinsic differences in the activation state between tissue resident and alveolar macrophages. It is notable that the study by Soroosh and colleagues found that tissue resident macrophages expressed high levels of retinal dehydrogenase (RALDH1 and RALDH2), which was corroborated by the finding of elevated levels of ALDH1 (synonymous with RALDH1) in the alveolar macrophages. The common theme linking these two studies is that lung macrophages in various compartments can be tuned toward a phenotype that augments airway tolerance via pathways that involve retinoic acid. Collectively, these studies, which utilize models of asthma, have significant relevance to transplantation. Long-term results following lung transplantation are hampered by obliteration of the terminal airways, a pathology similar to that of chronic asthma. Hence, it is tempting to speculate that a new avenue in the prevention of chronic lung rejection could utilize methods that toggle lung mononuclear cells toward a phenotype that induces regulatory T cells. Dr. Neujahr is assistant professor of medicine and medical director of lung transplantation at Emory University in Atlanta. Dr. Bromberg is professor of Surgery and Microbiology and Immunology, and is the chief of the Division of Transplantation, University of Maryland Medical Center, Baltimore. He is also section editor for “Literature Watch.”