In this issue

AbstractCover imageThe cover image for this issue has been designed in honor of the 14th International Congress of Immunology (ICI, August 22–27, 2010; www.ici2010.org), to be held in Kobe, Japan. The Kanji characters were proposed by the organizers of the meeting, and represent the study () of immunity (), i.e. immunology (). Underneath, the characters for creativity (), dream (), and future () are shown and represent the concept that, with creativity and some inspiration, we may anticipate a bright future for immunological studies. The image is a composition of the classic Japanese woodprint Mount Fuji in Clear Weather (also known as Red Fuji) by Katsushika Hokusai and immunofluorescent staining of CD248 in wild‐type MEF, adapted from an article in this issue by Lax et al. (pp. 1884–1889)Negative feedback regulation of autoimmunity: The natural priming of Treg subsets unraveledAmong naturally occurring Treg, CD4+FoxP3− and CD8αα+TCRαβ+ subsets target disease‐mediating CD4+ T cells and facilitate recovery from experimental autoimmune encephalomyelitis, a prototype of multiple sclerosis. How Treg are primed to respond to their cognate antigens, derived from the Vβ8.2TCR expressed by the target cells, is not known. In this issue, Smith et al. demonstrate that DC uptake of apoptotic Vβ8.2+ T cells leads to (1) processing of antigenic determinants from the TCR and (2) presentation of these antigenic determinants in a manner that stimulates a CD4+ Treg response. Together with their previous finding, which showed that this mechanism is also involved in the priming of the Qa‐1‐restricted CD8αα+TCRαβ+ Treg, the authors propose a negative feedback regulation model whereby CD4+ Treg (3) provide help (IFN‐γ) to CD8+ Treg to (4) kill an activated target T cell. These findings may have implications for the development of DC‐based therapeutics for intervention in T cell‐mediated autoimmune diseases.pp. 1906–1915Novel role for Foxo1 in controlling marginal zone B‐cell developmentMembers of the Foxo subgroup of Forkhead Box transcription factors regulate many aspects of lymphocyte development and function. In this issue, Chen et al. identify a novel function of the murine Foxo1 gene in controlling development of the marginal zone (MZ) subset of mature B cells. Using a conditional knockout approach, the authors show that the deletion of Foxo1 in developing B cells results in an overproduction of MZ B cells, with a corresponding decrease in the frequency of follicular B cells. Furthermore, deletion of Foxo1 suppresses the defect in MZ B‐cell development in mice lacking the B cell co‐receptor molecule CD19. Studies have shown that CD19 signals through the lipid kinase PI3K and the protein kinase AKT, and that Foxo's function is suppressed by AKT. Altogether, these findings suggest a model in which suppression of Foxo1 function by CD19‐derived signals promotes MZ B‐cell development.pp. 1890–1896JAB1 modulates protein levels of IgA receptor complexThe receptor for immunoglobulin A, FcαR, is expressed on neutrophils and is a key player in IgA‐mediated immunity. FcαR is currently recognized for its promising role in antibody‐mediated tumor therapy. In this issue, Bakema et al. provide new insights into the molecular mechanism leading to modulation of FcαRI‐FcR γ‐chain protein expression levels through the discovery of a novel interacting molecule for the intracellular domain of FcαRI, JAB1. JAB1 (c‐Jun activating binding protein 1) was first identified as a co‐activator of AP‐1 transcription. In the current study, the authors demonstrate JAB1 binding to FcαRI in the FcαRI‐FcR γ‐chain complex, which results in the modulation of FcαRI cell surface expression, rather than regulation of FcαRI‐induced transcriptional activity. Specifically, ectopic expression of JAB1 increases FcαRI surface expression, whereas the JAB1 knock‐down diminishes FcαRI surface protein levels and total FcR γ‐chain levels. Thus, this novel report demonstrates the functional consequences of JAB1 interaction with the cytosolic domain of FcαRI.pp. 2035–2040Ligand dimensions: A key factor in delivering signals to lymphocytesCell–cell contacts are pivotal in regulating immune cell function, and it has been proposed that size‐dependent protein segregation at the contact interface is an important mechanism for delivering signals to lymphocytes. For example, segregation of tyrosine phosphatases away from phosphotyrosine signalling motifs could help trigger cellular responses. In this issue, Brzostek et al. assess the role of ligand dimensions in delivering signals to murine NK cells. The authors previously demonstrated the critical importance of the small size of the TCR‐pMHC complex in triggering CD8+ T‐cell responses. In the current work, by increasing the dimensions of both activating and inhibitory ligands for murine NK cells, the authors show that ligand dimensions are also important in controlling NK‐cell responses. Together, these findings suggest that size‐dependent protein segregation is a fundamental mechanism of receptor triggering on different types of lymphocytes.pp. 2050–2059When the brakes are off, Btk and IL‐6 drive autoantibody productionThe autoimmune disease systemic lupus erythematosus (SLE) is characterized by the presence of autoantibodies that deposit in tissues. The ensuing inflammation can result in organ failure and potentially death. In this issue, Gutierrez et al. use Lyn‐deficient mice, which spontaneously develop a lupus‐like disease, to define two checkpoints that control the production of these autoantibodies. The authors show that, first, plasma cells accumulate in the periphery, leading to IgM autoreactivity against a broad range of self‐antigens. Subsequently, a subset of autoreactive B cells undergoes class switching to produce IgG autoantibodies, which are specific for a limited set of antigens commonly targeted in SLE. Interestingly, both processes require the tyrosine kinase Btk, but the class switching also depends on IL‐6. These data indicate that plasma cell accumulation and widespread IgM autoreactivity are not in themselves sufficient for the production of potentially pathogenic IgG autoantibodies. This study also identifies Btk, IL‐6, and these novel checkpoints as potential therapeutic targets for SLE.pp. 1897–1905