AbstractCover imageThe cover image depicts multi‐nucleated osteoclasts stained for tartrate‐resistant alkaline phosphatase (maroon colour) after in vitro differentiation from bone marrow myeloid cells. The image was taken from the article of Chen et al. (pp. 2845–2854), in which the authors demonstrate that the proinflammatory IL‐12 family cytokine, IL‐23, up‐regulates RANK expression in myeloid precursor cells and sensitizes cells for commitment to the osteoclast lineage. magnified imageA new angle in IL‐4 and IL‐12/ IFN‐γ antagonismThe ability of IL‐4 to antagonize anti‐tumour immunity is well‐recognized. What is less known however, is the role of IL‐4 in effector CD8 T cell trafficking. In this issue, Sasaki et al. show that IL‐4 suppresses the migration of protective CD8 T cells into tumor lesions. IL‐4 is expressed by various immune cells, as well as cancer cells. In tumor‐bearing animals, IL‐4 suppresses expression of the integrin VLA‐4. Suppression of VLA‐4 renders anti‐tumor CD8 effector T cells incapable of binding to their molecular counterpart, vascular cell adhesion molecule‐1 (VCAM‐1) that is expressed on the tumor‐associated vasculature. As a consequence, these anti‐tumor effector T cells fail to infiltrate tumor and prevent disease progression. Interestingly, the inhibitory effect of IL‐4 on VLA‐4 expression is reversed by IL‐12 but not IFN‐γ. The current results suggest that there may be yet another level to the intricacies of IL‐4, IL‐12 and IFN‐γ interactions. magnified imageMalaria parasites impair the host immune systemMalaria is famous amongst immunologists for its chameleon‐like camouflage ability and evasion of the immune system. In this issue, Jangpatarapongsa et al. explore the various mechanisms exploited by malaria parasites to elude the immune system. Acute Plasmodium vivax infection leads to activation of two Treg subpopulations, FOXP3+ Treg and Tr1 cells. The authors report an association between the level of Treg, IL‐10, plasmacytoid DC and myeloid DC during acute P. vivax malaria. While the overall levels of DC were reduced, the balance between the two DC types was found to be altered. These findings indicate immunosuppression of both cell‐ and antibody‐mediated immunity resulting in hindered parasite clearance. magnified imageYou are what you eat: Disrupted cells interfere with TLR‐mediated DC activationEffective anti‐tumour adaptive immunity requires efficient delivery of tumor‐associated antigens in the context of appropriate innate immune activation. Both freeze‐and‐thaw‐disrupted tumour cells and DC activation by TLR ligands have been studied extensively for antigen delivery and innate immune activation, respectively. Yet, little is known about DC activation in response to TLR ligands in the presence of freeze‐and‐thaw disrupted tumour cells. In this issue, Tirapu et al. report that disruption of membrane integrity does not affect the uptake of tumour cell material by DC, but suppresses the responsiveness of DC to TLR‐mediated activation. The inhibitory activity associated with disrupted cells is neither cell type‐ nor species‐specific, is instantly accessible upon freeze‐and‐thaw disruption, and appears to be independent of phosphatidylserine‐mediated inhibition of DC activation. magnified imageOf mice and men: CD146 and CD56 expression by NK cellsCD146/MCAM is an adhesion glycoprotein expressed preferentially on endothelial and some tumor cells. In this issue, Despoix et al. show that, within mouse lymphocytes, CD146 expression is restricted to a subset of NK cells. Human NK cells may be divided into two subsets according to their expression of CD56: the cytotoxic CD56dim subset is mainly located in the spleen and peripheral blood while the poorly cytotoxic CD56bright subset is mainly found in the lymph nodes and tonsil. In contrast, mouse NK cells do not express CD56 and their maturation is determined by expression of CD27 and CD11b: the CD27dullCD11b+ NK cells correspond to the more mature NK cell subset. Despoix et al. present flow cytometry analyses showing that CD146 expression is acquired upon mouse NK cell maturation. As CD146 staining is brighter than CD27 or KLRG1 stainings, it can be used to more clearly discriminate between different mouse NK cell subsets. magnified imagePOLH is where it's A:TGerminal center B cells undergo a high frequency of point mutations at both C:G and A:T base pairs in immunoglobulin V genes. This hypermutation process is initiated by the activation‐induced cytidine deaminase (AID), which catalyzes the deamination of cytosine (C) to uracil (U) and generates a U:G lesion. Mutations at A:T are thought to be generated during error‐prone repair of the AID‐triggered U:G lesion and require DNA polymerase ç (POLH). Now Wang and colleagues show that POLH is a limiting factor for A:T mutations. Loss of one Polh allele led to a ∼50% reduction in A:T mutations in the germinal center B cells, in fact each type of base substitution was at a level intermediate of that found in Polh+/+ and Polh−/− mice. Moreover, the authors demonstrate for the first time that A:T mutations are important for efficient antibody affinity maturation. magnified image