In this issue


Cover image

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The cover features a histology image of a lung section from a C57BL/6 mouse intranasally infected with influenza virus. The hematoxylin and eosin-stained section shows substantial cellular influx into airways 6 days after exposure to influenza virus, which is confirmed by flow cytometry to include CD3NKp46+NK1.1+CD127 NK cells. The image is taken from the article by Zhou et al. (pp. 929–938) in which the authors show that NK cells may exacerbate lung pathology during influenza infection in mice. Zhou et al. also show that NK-cell-induced pathology occurs with high-dose, but not low-dose influenza challenge, indicating that with severe influenza infections, NK cells may induce pathology that promote morbidity and mortality.

Gimme some TREM-1 to activate T cells

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DCs are central regulators of innate and acquired immunity and their functions can be modulated by the hypoxic environment in some pathologic sites. TREM-1, a member of the Ig superfamily of immuno-receptors, has been recently identified as a new marker of hypoxic DCs. In this issue, Pierobon et al. show that TREM-1 is induced in human immature DCs generated under chronic hypoxia (H-iDCs) and is involved in their functional reprogramming. The authors show that TREM-1 engagement triggers H-iDC phenotypic and functional properties typical of mature cells, including the upregulation of the chemokine homing receptors CCR7 and CXCR4 and the T-cell costimulatory molecules CD83 and CD86, and the secretion of proinflammatory, Th1/Th17 cell-priming cytokines and chemokines. Trem-1 induced H-iDC maturation results in the stimulation of allogenic T-cell proliferation and differentiation towards a Th1/Th17 direction. These results identify TREM-1 induction by hypoxia as a novel mechanism of regulation of Th1/Th17-cell polarization by DCs generated at hypoxic sites.

Policing CD4-CD8 differentiation in the thymus: Gata3 turns to repression

How helper (CD4+) and cytotoxic (CD8+) T cells differentiate in the thymus from CD4+CD8+ ‘double-positive’ thymocytes is not yet understood. Previous studies showed that two transcription factors, Thpok and Runx3, are important for CD4+ and CD8+ cell differentiation respectively, and mutually repress their expression in mature thymocytes. How then is their expression regulated in immature precursors which undergo lineage differentiation? In this issue, Xiong et al. place the spotlight on Gata3, a transcription factor transiently upregulated in CD4+ cell precursors upon T-cell antigen receptor (TCR) engagement by thymic MHC class II molecules. Gata3 was known to promote CD4+ cell differentiation, in part because it is needed for Thpok expression. Xiong et al. show that Gata3 transiently represses Runx3 gene expression and thereby contributes to prevent the aberrant differentiation of CD4+ cell precursors into CD8+ T cells in mice. These findings reinforce the role of Gata3 as a critical pivot of CD4-CD8 lineage differentiation.

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Salmonella, Type B CD4+ T cells and autoimmunity — is there a link?

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Microbes are implicated in the development of a variety of autoimmune conditions. A population of CD4+ T cells exists in the periphery that only recognize pre-processed peptide antigen. These “Type B” CD4+ T cells have escaped negative selection and have been recently linked to the development of autoimmune diabetes. In this issue, Jackson et al. show that exposure of murine bone-marrow derived dendritic cells to Salmonella polarizes peptide-MHC class II presentation towards a Type B T-cell response. In heavily infected BMDCs, this polarization may be further promoted by the downregulation and reduced presentation of peptide-MHC class II conformers recognized by conventional “Type A” CD4+ T cells. This study is the first to assess the role of Type B CD4+ T cells in infection and may suggest a mechanism by which Salmonella infection could lead to a breakdown in immunological tolerance.

Helper T cells develop side-by-side after early polarization

Helper T-cell differentiation is an important step in the induction of adaptive immune responses. By adopting specific phenotypes, these cells produce distinct sets of cytokines that regulate different immune effector mechanisms. In this issue, van den Ham et al. show that murine Th cells first differentiate into a particular phenotype and then further develop their effector functions. By generating sequential microarray-assisted transcriptome snapshots of developing Th1 and Th2 cells, the authors demonstrate that Th phenotypes diverge away from each other already during the first day of development. Sub-sequently, Th1 and Th2 cells maintain a constant developmental distance between them, i.e., Th1 and Th2 differ as much from each other on day 1 as on day 4 post-activation. The Th snapshots also show that Th differentiation genes consist of a constant ‘core response’ set, and a variable ‘turnover’ set. Analysis showed that members of the Batf transcription factor family are associated with Th1 and Th2 differentiation.

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STUB1 is essential for T-cell activation by ubiquitinating CARMA1

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Ag engagement triggers lymphocyte activation and proliferation by activating several transcription factors, including NF-κB. Caspase recruitment domain-containing membrane-associated guanylate kinase protein 1 (CARMA1) is an essential adaptor protein in AgR-triggered NF-κB activation. In this issue, Wang et al. identify stress-induced-phosphoprotein 1 homology and U-box containing protein 1 (STUB1) as a CARMA1-associated protein in the HEK293 and Jurkat E6 cell lines. The authors show that downregulation of STUB1 expression markedly diminishes TCR-induced canonical NF-κB activation and IL-2 production, and abolishes the endogenous ubiquitination of CARMA1 induced by TCR stimulation. Furthermore, as a U-box containing E3 ubiquitin ligase, STUB1 catalyzes K27-linked ubiquitination of CARMA1. These findings provide the first evidence that ubiquitination of CARMA1 by STUB1 promotes TCR-induced NF-κB signaling, and offer new insight into the mechanism responsible for control of aberrant T-cell activation.

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