In this issue

Abstract

AbstractCover imageThis issue's cover image depicts in vitro cell‐contact between adipose‐derived stromal cells (ASC) and PBMC, taken from Quaedackers et al. (pp. 3436–3446). In this article, the authors explore the contact‐dependent effect of mesenchymal stromal cells on immune cells, and demonstrate that ASC exert immunomodulatory effects by inhibiting both CD8+ and CD4+ T cell responses. magnified imageCD8+LAP+ cells join the Treg tango!pp. 3423–3435Regulatory T cells (Treg) are pivotal in the maintenance of immune tolerance. Although long recognized, CD8+ Treg remain poorly characterized. In this issue, Chen et al. identify a novel CD8+ Treg population characterized by cell surface expression of the latency‐associated peptide (LAP). Unlike other CD8+ Treg, CD8+LAP+ Treg are unique, as they are both TGF‐β‐ and IFN‐γ‐dependent. It is likely that CD8+LAP+ cells, by producing TGF‐β and IFN‐γ, establish a regulatory milieu by which CD8+LAP+ cells facilitate their immunomodulatory effects. The identification of CD8+LAP+ cells represents an important step in the investigation of Treg populations and may begin to explain unresolved issues in autoimmunity. For example, it is known that IFN‐γ‐deficient animals have a more severe form of EAE. Given the findings in this report, this may in part be related to the loss of suppressive capacity of the IFN‐γ‐dependent CD8+LAP+ Treg. magnified imageClever‐1/Stabilin‐1 – a multifunctional traffic lightpp. 3477–3487Immune cell trafficking between blood and lymphoid organs is essential for the proper functioning of the immune system. Mechanisms mediating lymphocyte entrance from the blood into the lymphoid organs and leukocyte trafficking to sites of inflammation are well known. On the contrary, molecular interactions mediating lymphocyte trafficking from the periphery via the afferent lymphatics into the draining lymph nodes and their exit from the lymph nodes are poorly characterized. In this issue, Karikoski et al. demonstrate that a scavenger molecule, Clever‐1/Stabilin‐1, mediates trafficking of lymphocytes to the draining lymph nodes via the afferent lymphatics. The authors also show that targeting inflammation‐induced Clever‐1/Stabilin‐1 on blood vasculature reduces migration of all leukocyte subtypes to the site of inflammation. Good news for potential therapeutic application is that despite marked anti‐inflammatory efficacy, bacterial clearance is not significantly compromised by inhibiting Clever‐1/Stabilin‐1. magnified imageSegregation of IL‐17‐ and IFN‐γ‐producing γδ T cells effector lineagespp. 3488–3497γδ T cells are emerging as the main producers of the pro‐inflammatory cytokine IL‐17 in immediate response to bacterial and fungal infection. On the contrary, CD4+ Th17 cells are rare during the early phases of immune responses. In this issue, Haas et al. describe two mutually exclusive markers, CC chemokine receptor 6 (CCR6) and the C‐type lectin NK1.1, which define contrasting effector concepts of γδ T cells that secrete either IL‐17 or IFN‐γ, respectively. The authors propose that both γδ effector cell types already exist within the adult thymus, suggesting a developmental selection. Both γδ effector populations show a high prevalence in peripheral lymph nodes but not in the gut epithelial tissues. Interestingly, IL‐17 production by γδ T cells was more TCR dependent than their IFN‐γ secretion. In conclusion, the findings of Haas et al. will contribute to further defining functionally distinct γδ T cell effector lineages. magnified imageTh17 and nTreg responses in the lung: A balancing actpp. 3307–3314Tight regulatory mechanisms are essential for the maintenance of immune homeostasis and limitation of potentially damaging inflammatory responses elicited by effector T cells. Th17 cells mediate autoimmunity, inflammation and mucosal host defence against pathogens. In this issue, Jaffar et al. demonstrate that Th17 cells, in response to antigen inhalation, cause an increase in airway hyper‐reactivity (AHR) and elicit pulmonary inflammation that is typified by neutrophilic infiltration, B cell recruitment and elevated polymeric Ig levels in the airways. Transfer of antigen‐specific Foxp3+ nTreg markedly reduce the Th17‐induced lung inflammatory responses and the number of IL‐17 expressing antigen‐specific T cells, but does not reduce AHR. Moreover, the regulation appears restricted to the lung, since limited numbers of Treg migrate to the lung draining lymph nodes. These results provide new insights into how Th17 responses are limited and may facilitate development of novel approaches for controlling Th17‐induced chronic inflammatory responses. magnified imageHIF‐1a in IgE‐mediated primary human basophil responsespp. 3511–3519Basophils has a pivotal role in regulating chronic allergic inflammation as well as angiogenesis. In this issue, Sumbayev et al. demonstrate for the first time that IgE‐mediated activation of primary human basophils results in protein accumulation of the α subunit of hypoxia‐inducible factor 1 (HIF‐1α), which is differentially regulated compared to signals controlling histamine release. HIF‐1α facilitates cellular adaptation to hypoxic conditions such as inflammation and tumour growth by controlling glycolysis, angiogenesis and cell adhesion. Activated in a MAP kinase‐dependent manner, HIF‐1α is essential for the expression of vascular endothelium growth factor (VEGF) in basophils. In addition, HIF‐1α protein alters IgE‐induced ATP depletion and thereby supports the production of the pro‐allergic cytokine IL‐4. magnified image