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The mediators that drive the progressive phase of multiple sclerosis remain undefined. Weiner and colleagues find that 15α-hydroxycholestene is expressed abundantly only during progressive multiple sclerosis and activates macrophages, microglia and astrocytes via poly(ADP-ribose) polymerase 1.
The gut immune system distinguishes commensal from dangerous microbes. Lee and colleagues delineate a pathway that 'fine tunes' the production of microbicidal reactive oxygen species to combat infections efficiently while tolerating commensal microbes.
In vitro studies suggest that the adaptor TANK is needed for the production of type 1 interferon. Using TANK-deficient mice, Akira and colleagues instead find that TANK negatively regulates Toll-like receptor and B cell antigen receptor signaling in vivo.
Expression of peripheral tissue antigens may be important for peripheral T cell tolerance. Fathman and colleagues demonstrate involvement of the transcription factor Deaf1 in maintaining this expression and link a Deaf1 isoform with type 1 diabetes.
B cell antigen receptors containing immunoglobulin G (IgG) or IgE, but not those containing IgM, show enhanced signaling. Wienands and colleagues trace this boosted signaling capacity to conserved IgG and IgE cytoplasmic tyrosine residues that recruit the adaptor Grb2.
In response to some signals, dendritic cells can become tolerogenic. Rabinovich and colleagues show that galectin-1 drives the differentiation of tolerogenic DCs via a circuit involving interleukins 27 and 10.
Patients infected with human immunodeficiency virus (HIV) have profoundly dysfunctional T and B cell populations. Cerutti and colleagues show that HIV-infected macrophages form long-range conduits that deliver the immunosuppressive HIV protein Nef to distal B cells, inhibiting their function.
SAP family adaptors, including SAP, EAT-2 and ERT, individually influence natural killer cell function. Veillette and colleagues show that natural killer cells lacking all three adaptors fail to eliminate unwanted hematopoietic cells.
The polarization of naive CD4+ T cells to become T helper type 2 cells requires the transcription factor GATA-3. Sen and colleagues show that T cell antigen receptor signals induce interleukin 4–independent but TCF-1–β-catenin–dependent early expression of GATA-3.
New work explains how the interferon-γ-regulated GTPase Irgm1 on phagosomes responds to intracellular signaling and recruits the 'machinery' for fusion with lysosomes. This pathway overlaps a signaling route controlled by bacteria to prevent the fusion of phagosomes with lysosomes.
The molecular mechanism by which thymocytes are positively selected remains incompletely understood. Three studies add a new piece to the positive selection puzzle.
Jawless fishes, the 'sister' group of jawed vertebrates, use leucine-rich repeat–containing proteins as antigen receptors. New work shows that the two isotypes of variable lymphocyte receptors are expressed in distinct lymphocyte lineages, which indicates that lymphocytes resembling T cells and B cells are an ancient feature of all vertebrates.
The thymic medulla provides a unique milieu for the induction of T cell tolerance. New work now provides a first glimpse of how thymocytes scan this microenvironment and thus maximize their chances of encountering self antigen.
Tipping the balance of early cytokine production can lead to lineage bias and, potentially, immune-mediated pathology. Mapping of a leishmania-susceptibility region has identified a gene that may determine the extent of T helper type 2 bias in naive helper T cells.
By identifying gene products whose knockdown is associated with phenotypic changes, large-scale RNA-mediated interference screens have demonstrated previously unknown components of biological pathways. This commentary provides general guidelines for using such screens to answer questions of immunological interest.
The stability of expression of the transcription factor Foxp3 in vivo has not been thoroughly assessed. Bluestone and colleagues find that Foxp3 expression can be unstable and that cells that lose Foxp3 expression can assume a proinflammatory autoaggressive phenotype.