In this issue

Abstract

AbstractCover imageThe cover picture features the hallmark set of scales representing the balancing of opinions in our Viewpoint series, with the schematic cell indicating the focus of this issue's series, i.e. Th17 cells/IL‐17. The schematic is taken from the article by Ouyang et al. (pp. 670–675) in which the therapeutic potential of drugs targeting the Th17 pathway for the treatment of autoimmune disease is considered. magnified imageCan bacterial antigens alter the adaptive immune response in the lung to fungal products?pp. 776–788Fungal antigens are ubiquitous within the environment and are triggers of allergic disease. Bacterial products are also frequently encountered within the environment and may alter antigen‐specific immunity. The consequences of simultaneous exposure to bacterial and fungal products on adaptive immunity in the lung is, however, not well documented. In this issue, Allard et al. demonstrate that molecules derived from heat‐killed Pseudomonas aeruginosa are sufficient to deviate the adaptive immune response to Candida ablicans through a TLR4‐independent but MyD88‐dependent mechanism. Thus, different types of microbial products within the airway can alter host‐adaptive immune response, potentially impacting the development of allergic airway disease to environmental fungal antigens. magnified imageExhaustion of invariant NKT cells in HIVpp. 902–922Invariant CD1d‐restricted NKT cells are susceptible to HIV‐1 infection and lost in many infected subjects. In this issue, Moll et al. investigate the characteristics of the NKT cells retained by some patients despite chronic HIV‐1 infection. The authors show that NKT cells preserved under these circumstances display poor proliferative capacity, low IFN‐γ production and exhibit elevated expression of the inhibitory receptor PD‐1. This functional phenotype is indicative of immune exhaustion suggesting chronic ongoing activation of these cells in vivo. These results help us understand the full impact of HIV‐1 on this arm of cellular immunity and suggest that these cells may be actively involved in attempts by the immune system to control HIV‐1. The data also limit the prospects of exploiting the adjuvant effect of these cells in immunotherapy or therapeutic vaccines in HIV‐1‐infected people. magnified imageCross‐priming defines immunodominancepp. 704–716Tumor‐specific CTL may be induced by either tumor cells directly in secondary lymphoid organs or professional APC (pAPC) may capture and process tumor antigen and induce CTL by cross‐priming. Although cross‐priming is accepted as the major pathway for CTL induction, direct CTL induction by tumor cells has also been reported. In this issue, Pavelic et al. demonstrate that only imunodominant epitopes induce CTL by cross‐priming, whereas CTL responses to subdominant epitopes depend on direct presentation of the epitopes on MHC class I of the tumor cell. These data indicate that certain tumor‐associated antigens may not be detected by CD8+ T cells because of impaired cross‐priming and that the immunodominant or subdominant nature of a given tumor epitope is determined by its capacity to be cross‐presented by pAPC. magnified imageMCP‐2/CCL8 chemokine activity in inflammation and cancerpp. 843–857Chemokines activate leukocytes via G protein‐coupled receptors (GPCR) to regulate inflammation and tumor development. MCP‐2/CCL8 is a pluripotent CC chemokine binding several GPCR allowing recruitment of most leukocyte subtypes. MCP‐2/CCL8 upregulation requires combined TLR and cytokine stimulation, e.g. LPS and IFN‐γ, or dsRNA and IFN‐γ. In this issue, Struyf et al. demonstrate that this pro‐inflammatory phenomenon is counteracted by NH2‐terminal processing of MCP‐2/CCL8, which results in a double‐negative feedback, i.e. loss of GPCR signaling and antagonisation of intact chemokines via receptor blockade by MCP‐2/CCL8(6–75). In contrast to the potent anti‐tumoral capacity of the related MCP‐3/CCL7, MCP‐2/CCL8 failed to inhibit melanoma growth in vivo due to proteolytic processing. This study shows that such limited chemokine cleavage not only dampens inflammation but also limits the anti‐tumoral capacity of chemokines. Therefore, it is crucial to determine (via proteomics, rather than ELISA) whether a chemokine remains intact or is processed in vivo in order to predict its role in pathology. magnified imageActivation of latent TGF‐β is a unique property of Tregpp. 869–882The role of TGF‐β in Treg cell biology is complex, and still controversial. Most often, TGF‐β is viewed as driving the differentiation of the so‐called induced Treg, but it is also occasionally proposed as a mediator of suppression by both natural and induced Treg. The recent “three‐cell model” derived from mouse systems suggests that Treg produce latent TGF‐β, which requires activation via integrins on dendritic cells before it can regulate the response of other T cells. In this issue, Stockis et al. use human Treg clones stringently defined by the methylation status of gene FOXP3 to show that a unique feature of human Treg lies in their ability to transform latent TGF‐β into the bioactive form of the cytokine. The mechanisms of TGF‐β activation by human Treg remain to be determined, but may differ from those at play in other cell types. magnified image