Immunosuppressive viral proteins

Measles virus (MV) can cause profound immunosuppression, however, the mechanisms behind this remain elusive. In Immunity, Marie et al. use a mouse model to investigate the role of MV proteins in the generation of immunosuppression in vivo. MV proteins, in the absence of MV replication, could induce systemic immunosuppression via two pathways. One requires MV-nucleoprotein and its cellular receptor FcγR on dendritic cells (DCs) and the other involves virus envelope glycoproteins and the MV-hemagglutinin receptor, CD46. The MV proteins ablated hypersensitivity responses, decreased IL-12 production by DCs and impaired antigen-specific T cell proliferation. Thus, MV proteins can modulate DC function and affect the priming and effector phase of hypersensitivity, making them candidates for therapeutic use.

Immunity 14, 69–79 (2001)

Unoccupied stable β dimer

The cytokines GM-CSF, IL-3 and IL-5 use unique α subunit receptors but share a common βc receptor subunit. In Cell, Young and colleagues report the structure of the complete extracellular domain of the βc subunit at a 3 Å resolution. These cytokines are involved in the regulation of hematopoiesis and inflammation. GM-CSF and IL-3 are both broad-acting growth regulators, whereas IL-5 plays a unique role in the regulation of eosinophils. The subunit structure is unlike any class I cytokine receptor described previously. It forms a unique interlocking dimer structure and gives new insights into the mechanism of receptor activation.

Cell 104, 291–300 (2001)

PPARγ cholesterol efflux

The nuclear receptor PPARγ has been implicated in macrophage uptake of oxidized LDL. In Molecular Cell, Tontonoz and colleagues provide evidence that, in addition to lipid uptake, PPARγ regulates a cholesterol efflux pathway. This occurs via a transcriptional cascade mediated by nuclear receptor LXRα. Ligand activation of PPARγ induces LXRγ, which leads to induction of the transporter protein ABCA1. Transfer of PPARγ-deficient bone marrow into LDLR−/− mice results in a significant increase in atherosclerosis. The authors propose that macrophage PPARγ coordinates a complex physiological response to oxidized LDL and cholesterol removal through ABCA1.

Mol. Cell 7, 161–171 (2001)

Mgat5, a negative regulator

Specific glycan structures play a role in lymphocyte adhesion, recirculation and maturation. The enzyme Mgat5 catalyzes the addition of β1,6GlcNAc to N-glycans. Magt5-modified glycans bind galectins, proteins that restrict TCR mobility. In Nature, Demetriou et al. examined the role of Mgat5 in T cell immunity using Mgat5-deficient mice. These mice displayed kidney autoimmune disease, enhanced delayed hypersensitivity and an enhanced susceptibility to experimental autoimmune encephalomyelitis. Mgat5-deficient T cells showed enhanced ligand-dependent TCR recruitment, signal transduction, microfilament reorganization and proliferation. Pretreatment of wild-type T cells with lactose, a galectin competitor, also induced TCR clustering. These results suggest that the absence of Mgat5-modified glycans can lower T cell activation thresholds by enhancing TCR clustering. Thus, Mgat5-dependent galectin-glycoprotein lattice may act as a negative regulator of T cell activation. Dysregulation of Magt5 may increase susceptibility to autoimmune disease.

Nature 409, 733–739 (2001)

Exosomes help reject tumors

T cell–mediated anti-tumor responses require DC presentation of tumor-antigen peptides on MHC class I. A study by Wolfers et al. in the March issue of Nature Medicine identifies a new source of tumor antigens available for DCs. They show that exosomes, small membrane vesicles secreted by cells, isolated from tumor cells are taken up by DCs. Exosomes display a discrete set of molecules involved in antigen presentation, including MHC class I and II and costimulatory molecules. DCs, loaded with tumor-derived exosomes, induce potent CD8+ T cell–dependent anti-tumor responses to established syngeneic and allogeneic tumors. Exosomes from tumor cells may represent a source of tumor-rejection antigens relevant for immunotherapy.

Nature Med. 7, 297–303 (2001)

MHC signaling through Igα-Igβ

Paired molecules on T and B cells mediate adhesion and signal transduction events during cognate T-B interactions. The TCR-pMHC class II interaction is central among these interactions, transducing signals that lead to Src family kinase activation, Ca2+ mobilization and proliferation. In Science, Cambier and colleagues. investigate the mechanism by which TCR-pMHC class II interaction leads to B cell activation. MHC class II molecules associate with Igα-Igβ heterodimers after antigen stimulation of resting B cells and function as signal transducers upon MHC class II aggregation by TCR. Class II MHC-associated Igα-Igβ heterodimers are derived, but distinct, from BCRs. Thus, these data show that Igα-Igβ heterodimers are sequentially used to transduce both antigen and cognate T helper cell signals.

Science 291 (2001)

IKKα and B cells

IκB kinase (IKK) α and β phosphorylate IκB proteins resulting in NF-κB activation. These highly homologous kinases play differential roles in vivo. In the Journal of Experimental Medicine, Akira and colleagues analyze the in vivo role of IKKα in hematopoietic cells by generating bone marrow chimeras with a transfer of fetal liver cells from mice obtained by intercrossing IKKα+/− mice. IKK−/− chimeras exhibited a decrease in mature B cells, serum immunoglobulin and impaired antigen-specific immune responses. The splenic microarchitecture, including germinal center formation, was disrupted. IKKα−/− B cells exhibited enhanced cell death, impaired mitogenic responses and reduced NF-κB activity in vitro, whereas B cell turnover rate was increased in vivo. Bcl-2 expression could only partially rescue impaired B cell development. Thus, IKKα is critical for mature B cell development and function.

J. Exp. Med 193, 417–426 (2001)