The cover image of this issue consists of a confocal image of a mediastinal draining lymph node (MdLN) section, taken 5 days post-infection of C57BL/6 mice with DsRed-expressing Brucella (red). Md1N sections were also stained for lysozyme (green) and MHCII (blue). This image was taken from Archambaud et al. (pp. 3458–3471). In this article the authors investigate the initial innate immune response that follows intranasal inoculation of Brucella abortus in the mouse. The authors demonstrate that alveolar macrophages are critical regulators of the initial innate immune response against Brucella within the lungs, and that pulmonary DC and alveolar macrophages play distinct roles in controlling initial pulmonary Brucella infection.
NOD1 contributes to intracellular pathogen clearance in the lung
The host immune response to Legionella pneumophila, an important cause of bacterial pneumonia, is regulated by several classes of innate immune receptors. With the exception of NAIP5 and IPAF, the contributions of cytosolic receptors to host response against Legionella are poorly understood. In this issue, Berrington et al. use an animal model of aerosolized infection to investigate the role of the intracellular pathogen receptors NOD1 and NOD2 in the detection of, and host immune response to, L. pneumophila. The authors report that both NOD1 and NOD2 are able to detect Legionella in vitro, but that only NOD1 contributes to the host immune response and the control of bacterial clearance in vivo. Specifically, the authors demonstrate that NOD1 is important for the early increase in proinflammatory cytokine production, as well as the early recruitment of phagocytic cells to the alveolar space. Furthermore, NOD1 enhances bacterial clearance from the lung at later timepoints. These findings suggest a non-redundant role for NOD1 in the host innate immune response against Legionella in the lung.
TLR circumvent DAP12-mediated regulation in mast cells
In mast cells, TLR agonists both induce cytokine production and enhance the antigen-mediated response. However, unlike antigen, TLR agonists do not induce degranulation. Recent reports have indicated that, by recruiting the tyrosine kinase Syk, DAP12, a small transmembrane protein that possesses a single ITAM motif, affects TLR-induced responses in certain cells of the hematopoietic lineage, including dendritic cells and macrophages. In this issue, Smrž et al. investigate whether DAP12 similarly influences TLR-mediated responses in mast cells. Surprisingly, the authors report that, although DAP12 is expressed in mast cells and can recruit Syk upon phosphorylation, the TLR- and antigen-mediated cytokine production in mast cells neither require, nor are modulated by, DAP12. These results suggest that the role of DAP12 in TLR-mediated cellular responses is cell type-dependent. The authors hypothesize that the inability of TLR to utilize DAP12 to recruit Syk in mast cells may provide an explanation as to why TLR do not induce mast cell degranulation.
SIRP-α+ DC: New therapeutic targets in asthma?
DC subsets with opposite functions have been identified in the airways. On one side, CD103+ SIRP-α−DC and plasmacytoid DC have been described as the “good guys”, promoting viral clearance and tolerance to inhaled antigens, respectively. On the other side, SIRP-α+ DC are immunogenic and are described, in a pathologic situation, as the “bad guys”, that induce airway inflammation and Th2 response. In this issue, Raymond et al. show that targeting SIRP-α/CD47 interaction with a CD47-Fc fusion molecule directly inhibits SIRP-α+ DC trafficking to the draining lymph nodes, without affecting the migration of the other airway DC subpopulations. The authors demonstrate that, as an indirect consequence, CD47-Fc-treated mice do not develop allergic airway inflammation and Th2 response. Moreover, the authors show that SIRP-α ligation by CD47-Fc does not impair DC Ag uptake, Ag presentation, Th2 priming and effector function in vitro. Based on these findings, the authors propose that targeting the CD47/SIRP-α axis may offer previously unknown novel therapeutic perspectives for allergic asthma.
Impaired Treg migration in multiple sclerosis
Naturally occurring Treg (CD4+ FoxP3+) are key regulators of the immune response, dampening autoimmunity and inflammation. By close interaction with the antigen-presenting cells, Treg are able to suppress the activation and expansion of effector T cells within the secondary lymphoid tissues, as well as at the sites of inflammation. As Treg represent only 5% of the CD4+ T-cell population, Schneider-Hohendorf et al. set out to investigate whether Treg present features that compensate for their lower numbers. In this issue, the authors describe an enhanced migratory capacity of murine and human Treg, when compared to their effector counterparts. However, the authors demonstrate that, in the context of multiple sclerosis, Treg lose this feature and cannot surpass effector cells in migratory rates under steady state conditions. This impairment in Treg-migratory capacity adds another dimension to the known Treg defects found in multiple sclerosis, further underlining the important role of Treg in autoimmunity.
Novel function for the immunoproteasome in T-cell survival
20S proteasomes are protein-degrading machineries with 14 different subunits. The three active site-bearing subunits are replaced by cytokine-inducible homologues, when the cells are stimulated with IFN-γ or TNF-α, to form the so-called “immunoproteasomes.” Since the discovery of the immunoproteasomes 20 years ago, it has been assumed that the sole function of these subunit exchanges is to alter protein cleavage, in order to generate more peptide ligands for presentation on MHC class I. Recently, it has been proposed that the immunoproteasomes are also involved in Th17-differentiation and in cytokine regulation. In this issue, Moebius et al. use T-cell transfer experiments into virus-infected mice to show that T cells lacking either of the three immunosubunits fail to persist in the recipient mice. Immunoproteasome-deficient CD8+ and CD4+ T cells die in the virus-infected host mice, whereas B cells largely persist. The authors provide evidence that this loss of immunoproteasome-deficient T cells after transfer is not due to the rejection of donor T cells by the host, but rather reflects an essential role of the immunoproteasomes in the survival of T cells in virus-infected mice.