Emerging evidence supports the concept that T helper type 17 (T H 17) cells, in addition to mediating autoimmunity, have key roles in mucosal immunity against extracellular pathogens. Interleukin-22 (IL-22) and IL-17A are both effector cytokines produced by the T H 17 lineage, and both were crucial for maintaining local control of the Gram-negative pulmonary pathogen, Klebsiella pneumoniae. Although both cytokines regulated CXC chemokines and granulocyte colony-stimulating factor production in the lung, only IL-22 increased lung epithelial cell proliferation and increased transepithelial resistance to injury.

Dendritic cells (DCs) are integral to differentiation of T helper cells into Th1, Th2 and Th17

Highlights d Antibody blockade of MerTK prevents apoptotic cell clearance by macrophages d MerTK blockade induces tumor-cGAS-and host-STINGdependent type I IFN response d Extracellular ATP facilitates transfer of tumor-derived cGAMP to TAMs via P2X7R d MerTK blockade increases tumor immunogenicity and enhances anti-PD-1/PD-L1 therapy

Dendritic cell (DC)-T cell interactions that underlie iTreg generation and airway tolerance are not well understood. Here we show that mice lacking CD11chi lung DCs but containing pDCs fail tolerization with inhaled antigen and cannot support Foxp3 induction in vivo in naïve CD4+ T cells. CD103+ DCs from tolerized mice efficiently induced Foxp3 in co-cultured naïve CD4+ T cells but pDCs and lung macrophages failed to do so. CD103+ DCs, but not pDCs or lung macrophages, upregulated expression of retinaldehyde dehydrogenase 2 (aldh1a2) that is key for production of retinoic acid, a co-factor for TGF-β for Foxp3 induction. Batf3−/− mice, selectively lacking CD103+ DCs, failed tolerization by inhaled antigen. Collectively, our data show that pulmonary tolerance is dependent on CD103+DCs, correlating with their ability to upregulate aldh1a2, which can promote FoxP3 expression in T cells.

Indoleamine 2,3 dioxygenase (IDO) has emerged as an important mediator of immune tolerance via inhibition of Th1 responses. However, the role of IDO in antigen-induced tolerance or allergic inflammation in the airways that is regulated by Th2 responses has not been elucidated. By using IDO ؊/؊ mice, we found no impairment of airway tolerance, but, surprisingly, absence of IDO provided significant relief from establishment of allergic airways disease, as evident from attenuated Th2 cytokine production, airway inflammation, mucus secretion, airway hyperresponsiveness, and serum ovalbumin-specific IgE. Myeloid dendritic cells isolated from lung-draining lymph nodes of mice immunized for either Th1 or Th2 response revealed fewer mature dendritic cells in the lymph nodes of IDO ؊/؊ mice. However, the net functional impact of IDO deficiency on antigen-induced responses was more remarkable in the Th2 model than in the Th1 model. Collectively, these data suggest that IDO is not required for the induction of immune tolerance in the airways but plays a role in promoting Th2-mediated allergic airway inflammation via unique effects on lung dendritic cells.tryptophan ͉ DC ͉ airways ͉ asthma I ndoleamine 2,3 dioxygenase (IDO) is an enzyme that mediates tryptophan catabolism into its metabolites including kynurenine or quinolinic acid (1-3). IDO protein is widely expressed in a variety of cell types including B cells, macrophages, eosinophils, dendritic cells (DCs), endothelial cells, and many types of tumor cells (2, 4-9). Because products of tryptophan metabolism are required for normal cell growth, depletion of IDO adversely impacts cell function (10). In the last decade, IDO has emerged as an important negative regulator in the immune system primarily because of its function in DCs, which play a quintessential role in antigen presentation to T cells (11). Several studies have implicated IDO in tumor-associated immune tolerance, and IDO has been associated with inhibition of Th1-mediated disease states (7,(11)(12)(13)(14)(15). Although IDO has been generally associated with Th1 inhibition, Trp metabolites were shown to induce Th2-like regulatory cells that suppressed Th1 pathology in experimental autoimmune encephalomyelitis, an experimental model for multiple sclerosis (14). Despite suggestion of differential effects of IDO on Th1 versus Th2 cells in these reports, no study has sufficiently explored this concept.There is little doubt that IDO plays a role in immune suppression and induction of T cell anergy. However, it has not been fully evaluated whether IDO-mediated immune suppression is pervasive under all circumstances. We investigated the role of IDO in established models of antigen-induced airway tolerance and inflammation by using IDO-deficient mice. We found that lack of IDO does not impair induction of immune tolerance induced by repeated antigen inhalation. On the contrary, IDO deficiency significantly attenuated the Th2 phenotype in the lungs in response to allergen provocation. When WT and IDO Ϫ/Ϫ mice were im...

Lim et al. demonstrate that protein deacetylase, Sirtuin 1, promotes autoimmunity by deacetylating RORγt increasing its transcriptional activity and promoting Th17 differentiation and function. Blockade or loss of Sirtuin 1 results in protection from multiple sclerosis-like disease in mice.

Aspergillus fumigatus is commonly associated with allergic bronchopulmonary aspergillosis in patients with severe asthma in which chronic airway neutrophilia predicts a poor outcome. We were able to recapitulate fungus-induced neutrophilic airway inflammation in a mouse model in our efforts to understand the underlying mechanisms. However, neutrophilia occurred in a mouse strain-selective fashion, providing us with an opportunity to perform a comparative study to elucidate the mechanisms involved. Here we show that TNF-α, largely produced by Ly6c + CD11b + dendritic cells (DCs), plays a central role in promoting IL-17A from CD4 +

The ubiquitous fungus Aspergillus fumigatus is associated with chronic diseases such as invasive pulmonary aspergillosis in immunosuppressed patients and allergic bronchopulmonary aspergillosis (ABPA) in patients with cystic fibrosis or severe asthma. Because of constant exposure to this fungus, it is critical for the host to exercise an immediate and decisive immune response to clear fungal spores to ward off disease. In this study, we observed that rapidly after infection by A. fumigatus, alveolar macrophages predominantly express Arginase 1 (Arg1), a key marker of alternatively activated macrophages (AAMs). The macrophages were also found to express Ym1 and CD206 that are also expressed by AAMs but not NOS2, which is expressed by classically activated macrophages. The expression of Arg1 was reduced in the absence of the known signaling axis, IL-4Rα/STAT6, for AAM development. While both Dectin-1 and TLR expressed on the cell surface have been shown to sense A. fumigatus, fungus-induced Arg1 expression in CD11c+ alveolar macrophages was not dependent on either Dectin-1 or the adaptor MyD88 that mediates intracellular signaling by most TLRs. Alveolar macrophages from WT mice efficiently phagocytosed fungal conidia, but those from mice deficient in Dectin-1 showed impaired fungal uptake. Depletion of macrophages with clodronate-filled liposomes increased fungal burden in infected mice. Collectively, our studies suggest that alveolar macrophages, which predominantly acquire an AAM phenotype following A. fumigatus infection, have a protective role in defense against this fungus.