Showing papers by "Lucy Bird published in 2003"

Homing in on leukotrienes

Abstract: VOLUME 3 | OCTOBER 2003 | 777 To mediate an effective immune response, T cells must find their way to sites of infection or inflammation. Changes in T-cell homing patterns following activation are thought to result from changes in the expression of homing molecules, including adhesion molecules and chemokine receptors, however, data now show that this might not be the whole picture. Three articles in the October issue of Nature Immunology report that leukotriene B 4 (LTB 4 ) — an arachidonic-acidderived pro-inflammatory lipid — is also involved in T-cell recruitment. Andrew Luster and colleagues, who generated mice deficient for the main LTB 4 receptor BLT1, showed that LTB 4 could direct the recruitment of CD4 effector T cells. They showed that BLT1 was highly expressed by CD4 effector T-cell subsets differentiated in vitro under T helper 1 (T H 1)or T H 2-polarizing conditions and after activation in vivo. Expression of BLT1 enabled both subsets of CD4 effector T cells to move by chemotaxis towards a LTB 4 gradient, whereas naive cells were unaffected by the presence of LTB 4 . Both subsets of CD4 effector T cells also adhered to endothelial cells under flow when exposed to LTB 4 . They used their BLT1-deficient mice in an asthma model to show that the recruitment of early CD4 and CD8 T cells to the airways after aerosol challenge of previously immunized mice was dependent on the expression of BLT1. An important source of LTB 4 was shown by Vanessa Ott et al. to be activated mast cells — the sentinel cells of the tissues’ early warning system. They showed that activated mast cells could induce the migration of CD8 effector T cells through the production of LTB 4 . Therefore, LTB 4 seems to act as a link between the activation of innate immune cells and early recruitment of adaptive immune cells. Ulrich von Andrian’s group also investigated the response of CD8 T-cell subsets to LTB 4 . CD8 naive, effector and central memory T cells have distinct migratory properties in vivo; naive and central memory T cells home to secondary lymphoid tissues, whereas effector T cells migrate efficiently to inflamed tissues. The authors showed that CD8 effector T cells express high levels of BLT1, whereas CD8 memory T cells express low levels. BLT1-expressing CD8 effector T cells moved by chemotaxis towards LTB 4 , whereas naive and memory cells did not. By contrast, LTB 4 induced the rapid accumulation of both effector and memory T cells, but not naive cells, in postcapillary venules by promoting the transition from rolling to firm arrest. This effect depended on signals mediated through BLT1, as cells from the BLT1-deficient mice did not arrest in response to LTB 4 . Using a model of peritonitis, they showed that wild-type effector cells were three times more efficient at migrating to the inflamed peritoneal cavity than BLT1-deficient effector cells, further indicating an important role for LTB 4 –BLT1 interactions in the trafficking of CD8 effector T cells in vivo. Lucy Bird References and links ORIGINAL RESEARCH PAPERS Tager, A. M. et al. Leukotriene B4 receptor BLT1 mediates early effector T cell recruitment. Nature Immunol. 31 August 2003 (DOI: 10.1038/ni970) | Ott, V. L. et al. Mast cell-dependent migration of effector CD8+ T cells through production of leukotriene B4. Nature Immunol. 31 August 2003 (DOI: 10.1038/ni971) | Goodarzi, K. et al. Leukotriene B4 and BLT1 control cytotoxic effector T cell recruitment to inflamed tissues. Nature Immunol. 31 August 2003 (DOI: 10.1038/ni972) identifies these molecules as specific cell-surface ligands for DNAM1. The killing of untransfected CHO-K cells by the NK-cell line NK92 depends on NKp30 (another orphan receptor). But, when these cells were transfected with the gene encoding PVR or nectin-2, NK-cell killing could only be partly inhibited by an NKp30-specific antibody, with the remainder of the cytotoxic activity being inhibited by an antibody specific for DNAM1. The functional interaction between DNAM1 and PVR and/or nectin-2 was also shown to lead to NK-cell activity for tumour target cells. These experiments showed that the killing of tumour cells by polyclonal NK cells depends on many triggering receptors, with the relative contribution of DNAM1 binding to PVR or to nectin-2 depending on the tumour type and ligand/receptor availability. Kirsty Minton

HIV: Under pressure

Abstract: Babies have a hard time of it — not only do they have a bit of a struggle coming into the world, but also they are then particularly susceptible to various infections with viruses and bacteria. It is generally believed that neonatal susceptibility to infection is due to a developmental defect in immune function, particularly a delay in the maturation of effective T helper 1 (T H 1)-cell responses. But, little is known about how neonatal CD8 T cells respond to virus infection. Now, Marchant and colleagues show that neonates can generate a mature and functional CD8 T-cell response to infection with human cytomegalovirus (HCMV), which might have implications for the development of neonatal vaccines. Marchant and colleagues studied the functional capability of CD8 T cells in congenitally infected neonates. Fetal T cells at the 28-week stage showed characteristics of early differentiated cells, with numerous highly activated cells undergoing proliferation. Infected newborns had higher proportions of activated CD8 T cells than uninfected neonates, and repertoire analysis showed that HCMV infection had triggered the oligoclonal expansion of CD8 T cells. Analysis of expression markers showed that the T cells of newborns had the characteristics of antigen-experienced cells with a phenotype resembling that of memory cells. Intracellular staining of these T cells showed high levels of perforin and granzyme A, and the T cells had perforindependent cytolytic activity. The T cells were also able to produce antiviral cytokines, such as interferon-γ. So, fetal and neonatal CD8 T cells do seem to be able to respond to virus infections. These results indicate that there might be fewer developmental constraints on the CD8 T-cell compartment than on CD4 T cells, and although further work on the mechanisms of T-cell priming in neonates is necessary, it might be possible to develop neonatal vaccination for virus infections. Elaine Bell References and links ORIGINAL RESEARCH PAPER Marchant, A. et al. Mature CD8+ T lymphocyte response to viral infection during fetal life. J. Clin. Invest. 111, 1747–1755 (2003)