In this issue

Abstract Cover Pictures ‐ It has recently been shown that TLR are capable of regulating the differentiation of haematopoietic progenitor cells. Specifically, R848 (resquimod, a specific TLR7/8 agonist) is capable of stimulating the differentiation of human bone marrow CD34 + progenitors into myeloid DC. Sioud and Fløisand (pp. 2834–2846) investigate the differentiation induced by other TLR agonists (loxoribine (TLR7) and Pam 3 CSK 4 (TLR2)), as well as further investigating the effects of R848. The cover image (a composite, artificially coloured figure) is based on May‐Grünwald‐Giesma staining of the CD11c – CD14 – (green section of the image), CD11c + CD14 + (yellow section) and CD11c + CD14 – (red section) cell subsets induced following stimulation of CD34 + progenitors with R848 for seven days. Importantly, around 30% of cells of the CD11c + CD14 – subset display DC morphology (multiple fine dendrites) and, furthermore, this CD11c + CD14 – subset is shown to be capable of activating allogeneic T cells. New liaison in autoimmune disease: A link between IL‐15 and IL‐17 pp. 2744–2752 The interplay between cytokines can seem befuddling, but its dissection has proven incredibly valuable in the realm of autoimmune diseases, where anti‐cytokine treatments have proven remarkably effective in increasing the quality of life of patients. The cytokine IL‐15 is a proven culprit in a wide variety of autoimmune diseases, while the pro‐inflammatory cytokine IL‐17 is a relatively new face on the scene; however, IL‐17 has been implicated in the pathogenesis of collagen‐induced arthritis (CIA), a rodent model of human rheumatoid arthritis (RA), and IL‐17 may have a link to IL‐15. To better understand the relationship between IL‐17 and IL‐15, Yoshihara et al. analyze CIA in mice with genetically altered IL‐15: both the incidence and severity of CIA, as well as the levels of IL‐17 production, are increased in IL‐15 Tg mice, as compared to controls, while the reverse is observed in IL‐15 –/– mice. Interestingly, further investigation by Yoshihara et al. links the elevated IL‐17 levels to production by CD4 + T cells as a result of stimulation via IL‐15 and IL‐23. F4/80, a specific marker for…eosinophils?? pp. 2797–2802 The F4/80 antigen is a key marker for the identification of murine macrophages, and there really wasn’t any reason to think it wouldn’t be equally valuable for identifying human macrophages. Well, think again! Hamann et al. have generated an antibody specific for EMR1, the human molecule orthologous to murine F4/80, and find that it doesn’t bind to macrophages at all. Instead, the antibody (A10) proved highly specific for eosinophilic granulocytes. Who would have guessed?! Along the (long) line of cytokines in autoimmune diseases … what about IL‐33? pp. 2779–2786 A recent addition to the interleukins, IL‐33 (first described in 2005) has been linked to inflammatory pathology; however, although IL‐33 is known to induce the production of Th2‐associated cytokines ( e.g. IL‐5 and IL‐13), the mechanism behind its involvement in inflammatory conditions is unclear. Interestingly, its specific receptor is ST2, which is selectively expressed on a subset of Th2 but not Th1 cells, has strong associations with inflammatory conditions (soluble ST2 is elevated in a variety of human diseases e.g. asthma) and is an effective treatment for, among other conditions, CIA. Komai‐Koma et al. find that IL‐33 is a powerful chemoattractant for Th2 cells both in vitro , inducing morphological changes and migration into collagen matrices, and in vivo , attracting adoptively transferred ST2 + (but not ST2 – ) Th2 cells to a site of IL‐33 injection. Thus, via active recruitment of Th2 cells to inflammatory sites, IL‐33 may play a crucial role in maintaining chronic inflammation. Agonise me, don’t antagonise me: A case for PD‐1 in allograft tolerance pp. 2983–2990 All good immune responses must come to an end…and up‐regulation of molecules such as CTLA‐4 and PD‐1 upon T cell activation help make sure they do. Clinical exploitation of this mechanism might help control undesired immune responses, such as allograft rejection, hence the development of, for example, CTLA‐4Ig. In this light, Wang et al. study the requirement of PD‐1 and its inducible ligand PD‐L1 for allograft tolerance using PD‐1‐ and PD‐L1‐deficient mice, as well as PD‐1/PD‐L1 blocking mAb. In the absence of a functional PD‐1/PD‐L1 pathway, costimulation blockade ( via CD154 mAb/donor splenocyte transfusion or CD154/CTLA‐4Ig), which is normally effective in inducing allograft tolerance, is ineffectual, and acute allograft rejection results. A corresponding persistence of proliferation and cytokine production by PD‐1 –/– T cells is observed. Thus, inhibitory signals following PD‐1 ligation appear crucial for the generation of costimulation blockade‐induced allograft tolerance which is promising news for controlling immune responses following allograft transplantation. If you’re sick, turn up the heat! Hundreds of millions of years of evolution can’t be wrong pp. 2856–2867 In mammals, fever‐range temperatures promote homing to lymphoid organs (and subsequent immune surveillance) by increasing L‐selectin‐dependent adhesion to HEV via a mechanism involving IL‐6 as a cytokine mediator. Although L‐selectin activity has been identified in only mammals and birds, and mammals are unique in their well‐developed HEV axis, fever (or heat‐seeking behavior) during infection is beneficial to a wide variety of both endothermic and ectothermic species. To better understand the evolutionary conservation of fever‐range thermal stress, Appenheimer et al. analyze leukocytes from a variety of mammals, as well as avian (chicken), amphibian ( X. laevis ) and teleost ( O. mykiss ; rainbow trout) species, using cross‐species in vitro adherence assays. Thermally sensitive L‐selectin‐like binding activity controlled by a shared IL‐6 trans‐signaling mechanism was identified in all the species tested. Despite ∼450 million years of evolution of these species from a common ancestor, the febrile temperature response has remained pretty much the same… it says a lot about its importance for host survival!