Showing papers by "Lucy Bird published in 2012"

Mucosal immunology: IL-22 keeps commensals in their place

Abstract: Innate lymphoid cells help to retain commensal bacteria in anatomical niches and prevent systemic inflammation.

Gut microbiota influences liver disease.

Abstract: Changes in the gut microbiota owing to inflammasome deficiency promote chronic inflammatory liver disease.

Macrophages: Yolky beginnings

Abstract: Most tissue macrophages in mice are derived from the yolk sac and not from haematopoietic stem cells.

Viral immunity: Shelter from interferons.

Abstract: nism that explains how the innate immune system inhibits viral propaga­ tion but still allows the production of enough viral antigens to stimulate an effective adaptive immune response. The answer lies in a subset of macro­ phages that resists the anti viral effects of type I interferons (IFNs). Soon after systemic infection, viruses are captured by phagocytic innate immune cells, which sup­ press viral propagation through the production of type I IFNs. Indeed, in the case of mouse vesicular stomatitis virus (VSV), the authors showed that macrophages in the red pulp of the spleen and Kupffer cells in the liver effectively capture the virus and inhibit its replication in a type I IFN­ dependent manner. However, 7 hours after infection, replicating virus could be detected in CD169+ macrophages in the marginal zone of the spleen but not elsewhere. Further analysis of the marginal zone CD169+ macrophages showed that they express higher levels of ubiquitin­specific peptidase 18 (USP18) — which is known to inhibit type I IFN signalling — than F4/80+ macrophages from the red pulp. USP18 overexpression was found to be responsible for allowing VSV replication, as low amounts of viral proteins were detectable in CD169+ macrophages from Usp18–/– mice. Given that ultraviolet light­ inactivated, replication­deficient VSV generated poor antiviral B and T cell responses, the authors inves­ tigated the involvement of CD169+ macrophages in the generation of adaptive immune responses to VSV. Mice that were specifically depleted of CD169+ macrophages showed delayed and diminished B cell responses to VSV relative to control mice. Moreover, Usp18–/– mice infected with VSV had delayed antibody responses and reduced CD4+ T cell responses compared with infected wild­type mice. No such differences were observed if the mice were infected with replication­ deficient VSV, confirming that VSV replication in CD169+ macrophages was responsible for the induction of adaptive immune responses. Failure to generate strong adaptive immune responses led to the spread of the virus and death of the mice. So, by allowing viral replication in the pres­ ence of type I IFNs, marginal zone macrophages ensure the production of sufficient antigens for the activa­ tion of protective adaptive immune responses. Lucy Bird

Innate immunity: Epithelial cells ACT up in worm expulsion.

Abstract: Epithelial cells mediate immunity to helminths by promoting type 2 innate effector cell responses.

ADAM17 -- gatekeeper of the skin barrier.

Abstract: The metalloproteinase ADAM17 maintains the epidermal barrier through basal Notch activation.

T cell memory: Skin-deep memory.

Abstract: Skin-resident effector memory CD8+ T cells provide long-lasting immune protection in the skin.

Viral immunity: Lose TRAF1, lose control.

Abstract: defect that is associated with CD8+ T cell dysfunction in chronic viral infection. An acquired loss of expression of the signalling adaptor TNFR-associated factor 1 (TRAF1) from virus-specific CD8+ T cells during HIV infection in humans and during chronic lymphocytic chorio meningitis virus (LCMV) infection in mice decreases their ability to control the virus. Analysis of HIV-specific CD8+ T cells from HIV-infected donors revealed that TRAF1 expression was specifically reduced in these cells from chronically infected donors but not from recently infected donors or virus controllers. Further studies confirmed that TRAF1 expression levels decrease in HIV-specific CD8+ T cells over time and negatively correlate with viral load and the expression of programmed cell death 1 (PD1), which is a negative regulator of T cell function. Forced knockdown of TRAF1 expression in CD8+ T cells from virus controllers using small interfering RNA led to defective virus control of infected CD4+ T cells by these CD8+ T cells ex vivo. This defect could be overcome by simultaneous knockdown of the proapoptotic molecule BCL2-interacting mediator of cell death (BIM; also known as BCL2L11), which is known to be downmodulated in a TRAF1-dependent manner. Loss of TRAF1 expression was also found to impair the proliferation of HIVspecific CD8+ T cells in response to 4-1BB ligand (4-1BBL; also known as TNFSF9), the receptor for which signals through TRAF1. The authors similarly observed a selective loss of TRAF1 expression in virus-specific CD8+ T cells from mice infected with an LCMV strain that establishes a chronic infection, but not from mice infected with an acute LCMV strain. In addition, a role for TRAF1-dependent, 4-1BBL-mediated signalling in the control of early infection is consistent with the finding that 4-1BBL-deficient mice generated low numbers of virus-specific CD8+ T cells and had high viral loads early after infection with LCMV, but not at later stages of the infection. Next, the authors investigated the possible regulators of TRAF1 protein expression. Transforming growth factor-β (TGFβ) was found to induce TRAF1 protein loss through an endosome-dependent process and, conversely, interleukin-7 (IL-7) and other common γ-chain family cytokines upregulated TRAF1 protein expression in vitro. Accordingly, treatment of mice with recombinant IL-7 on day 21 after chronic LCMV infection restored TRAF1 expression in virus-specific CD8+ T cells. Moreover, mice that were treated with both IL-7 and an agonistic 4-1BB-specific antibody produced higher numbers of virus-specific CD8+ T cells following infection and showed improved virus clearance compared with each treatment alone. These effects were dependent on TRAF1, as no such response to the therapy was observed in TRAF1-deficient mice. In their final experiments, the authors showed that pre-transfer of TRAF1+ LCMV-specific memorylike CD8+ T cells into mice with chronic LCMV infection markedly reduced viral loads compared with pre-transfer of TRAF1–CD8+ T cells. This finding confirms that T cell-intrinsic TRAF1 expression is important for control of chronic LCMV infection. Lucy Bird

T cells: Steroids improve T cell fitness.

Abstract: Endogenous glucocorticoids promote the selection of thymocytes that have an appropriate affinity for self.

Immunotherapy: A killer combination

Abstract: Keeping virus-driven lymphomas in check Epstein–Barr virus (EBV) is rapidly cleared by the immune system, but it can persist in some cells for life. Under conditions of immunosuppression, B cells that are latently infected with EBV can undergo marked proliferation and malignant transformation. EBV latent membrane protein 1 (LMP1) is essential for the transformation of human B cells. Here, the authors generated a mouse model in which all B cells expressed LMP1. LMP1 B cells were efficiently deleted by T cells in immunocompetent animals, but they underwent marked clonal expansion and formed large B cell lymphomas in immunocompromised animals. Both CD4 and CD8 T cells contributed to immune surveillance of LMP1 B cells. Natural killer (NK) cells were also activated by LMP1 B cells, which expressed ligands for the NK cell receptor NKG2D. Indeed, treatment of tumour-bearing mice with an NKG2D–Fc fusion protein caused efficient lysis of LMP1 tumour cells, suggesting a possible new therapy for EBV-driven B cell lymphomas.

Tumour immunology: Keeping virus-driven lymphomas in check

Abstract: Keeping virus-driven lymphomas in check Epstein–Barr virus (EBV) is rapidly cleared by the immune system, but it can persist in some cells for life. Under conditions of immunosuppression, B cells that are latently infected with EBV can undergo marked proliferation and malignant transformation. EBV latent membrane protein 1 (LMP1) is essential for the transformation of human B cells. Here, the authors generated a mouse model in which all B cells expressed LMP1. LMP1 B cells were efficiently deleted by T cells in immunocompetent animals, but they underwent marked clonal expansion and formed large B cell lymphomas in immunocompromised animals. Both CD4 and CD8 T cells contributed to immune surveillance of LMP1 B cells. Natural killer (NK) cells were also activated by LMP1 B cells, which expressed ligands for the NK cell receptor NKG2D. Indeed, treatment of tumour-bearing mice with an NKG2D–Fc fusion protein caused efficient lysis of LMP1 tumour cells, suggesting a possible new therapy for EBV-driven B cell lymphomas.

Development: Pulling RANK.

Abstract: The development of medullary thymic epithelial cells and γδ T cells is linked through RANK signalling.