Elaine Bell

B7h and B7-H1: new members of the B7 family: Swallow, M.M. et al. (1999) B7h, a novel costimulatory homolog of B7.1 and B7.2, is induced by TNF-α. Immunity 11, 423–432; Dong, H. et al. (1999) B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat. Med. 5, 1365–1369

Two novel members of the B7 family, murine B7h and human B7-H1, have recently been identified. B7h was identified using a subtractive screen designed to isolate tumour necrosis factor α (TNF-α)-induced genes that are specifically regulated by NF-κB/Rel transcription factors, whereas B7-H1 was identified by searching an EST database for homologues of B7-1 and B7-2.The classic costimulatory molecules, B7-1 and B7-2, are constitutively expressed on dendritic cells and upregulated after activation on monocytes, macrophages, and B and T cells. B7h is expressed on antigen-presenting cells (APCs) but can also be expressed on other cell types in response to TNF stimulation. The inducible expression of B7h on non-APCs and the higher threshold of T-cell receptor activation required for costimulation via B7h, suggest a distinct functional role for B7h compared with B7-1 and B7-2. The authors speculate that instead of costimulating naive T cells, B7h may influence local tissue responses by costimulating T cells following their primary activation in lymph nodes.Both B7h and B7-H1 stimulate T-cell proliferation independent of CD28 and CTLA-4. However, B7h may interact with ICOS, a recently described homologue of CD28 and CTLA-4. B7-H1 also stimulates T-cell proliferation and increases cytokine secretion, especially interleukin 10 (IL-10); IL-2, although produced in small amounts, is necessary for B7-H1 costimulation. The data from these two papers suggest that, in contrast to B7-1 and B7-2, the newer members of the family might act as negative regulators of cellular immune responses.

TNF-R homologues in autoimmune disease

Gross, J.A. et al. (2000) TACI and BCMA are receptors for a TNF homologue implicated in B-cell autoimmune disease. Nature 404, 995–999Tumour necrosis factor (TNF) family members are important regulators of immune function and play a role in lymph node organogenesis, inflammatory responses and lymphocyte activation. Abnormal levels or decreased expression of TNF and related molecules are known to contribute to inflammatory disorders and autoimmune diseases. zTNF4 (also known as BAFF, BLyS, TALL-1 and THANK) is a recent addition to the TNF family.In the present study, Gross et al. describe the overexpression of zTNF4 in lymphoid cells of transgenic mice. The mice develop an autoimmune disease that resembles systemic lupus erythematosus. They exhibit elevated levels of serum IgG and IgM and have increased numbers of activated B cells in enlarged lymph nodes and spleen. zTNF4 transgenic mice also have elevated numbers of splenic B-1a cells, a population of cells that are known to predominantly produce self-reactive IgM antibodies. Gross et al. also show that circulating zTNF4 is more abundant in NZBWF1 and MRL-lpr/lpr mice, which are used as models for lupus-like diseases.Gross et al. have now identified two TNF-R homologues, TACI and BCMA, that bind to zTNF4 and are expressed predominantly on B cells and activated T cells. A zTNF4 decoy receptor was generated by fusing the extracellular portion of TACI to the constant region ‘tail’ of IgG. Treatment of NZBWF1 mice with the TACI-Ig fusion protein delayed proteinuria, decreased the number of peripheral B cells and suppressed the development of lupus-like disease in these animals.Following recent success using TNF decoy receptors to treat rheumatoid arthritis, zTNF4 now joins the growing ranks of potential targets for therapy of autoimmune diseases.

Distinct antigen processing pathway for CD1b molecules: Sugita, M. et al. (1999) Separate pathways for antigen presentation by CD1 molecules. Immunity 11, 743–752

Antigen presentation to T cells is a central facet of the adaptive immune response. Major histocompatibility complex (MHC) class I molecules bind peptides in the endoplasmic reticulum and present peptides derived from endogenous proteins, such as viral proteins. By contrast, MHC class II molecules bind to peptides derived from exogenous proteins in the late endosomal compartments. CD1 molecules are a family of β2-microglobulin-associated non-polymorphic glycoproteins that, in contrast to MHC class I and II molecules, have been shown to present lipid and glycolipid antigens, and GPI-linked proteins.Unlike other CD1 molecules, CD1a lacks the specific cytoplasmic tail motif that is known to induce localization of CD1 molecules to the endosomal compartment. In this study, Sugita and colleagues tested the hypothesis that CD1a might represent a processing pathway distinct from the other CD1 and MHC molecules. Using immunofluorescence microscopy and electron microscopy as well as functional studies, they were able to demonstrate functional and anatomical separation of the CD1a and CD1b processing pathways. Like MHC class II, CD1b molecules localize to late endosomal compartments and require vesicular acidification for function. By contrast, CD1a molecules were found to localize to the recycling compartments of the early endosomal pathway, and do not require acidification for function. Sugita and colleagues speculate that differential trafficking of the CD1 isoforms allows CD1 molecules to efficiently sample antigen from a variety of compartments, and detect microbes that may attempt to evade the immune response by avoiding localization in specific compartments, such as mycobacteria.

Murine embryonic survival depends on regulation of complement

Activation of the complement system is a feature of both the innate and adaptive arms of the immune response. As a component of natural immunity, complement activation leads to enhanced phagocytosis, clearance of immune complexes, chemotaxis of inflammatory cells and cell lysis. Although complement can bind to self tissues, cells are protected because they express proteins that inactivate complement. In humans, decay accelerating factor (DAF) and membrane cofactor protein (MCP) are involved in inactivation of complement components. In rodents, a third protein, Crry, is also involved in complement regulation.In this study, Xu and colleagues set out to generate Crry-knockout mice to investigate in vivo the role of Crry in protecting against complement attack. However, no live Crry−/− mice were recovered, indicating that Crry plays a crucial role in pregnancy. Crry−/− embryos died at day 10 after conception. Complement deposition was detected in both the embryo and placenta, as well as infiltration of inflammatory cells. Crossing the Crry+/− mice with C3−/− mice (in which complement is inactive) produced 27% of pups that were Crry−/−, indicating that complement activation was the cause of the embryonic lethality of the Crry−/− mice.Although mice possess DAF and MCP as well as Crry, neither DAF nor MCP are expressed in early embryos, leaving Crry as the crucial regulator of complement activation at this stage of murine development. Crry does not exist in humans, but DAF and MCP are both expressed in human placentas. Xu and colleagues propose that DAF and MCP play a similar role to Crry in controlling complement-mediated inflammation and tissue damage in early human pregnancy.

RTD-1: a new type of defensin

Tang, Y-Q. et al. (1999) A cyclic anti-microbial peptide produced in primate leukocytes by the ligation of two truncated α-defensins. Science 286, 498–502Innate immune mechanisms exist to provide an immediate response to microbial infection. Recent studies have revealed that innate defense mechanisms are remarkably conserved across species and exhibit some degree of specificity. Anti-microbial peptides, of which the defensins are one class, constitute a major component of innate defense, particularly in plants and insects. Vertebrate defensins, which fall into two structural classes α and β, are cationic molecules which act by preferentially disrupting microbial membranes.A recent paper in Science describes the isolation of a novel anti-microbial peptide from rhesus macaque neutrophils and monocytes, termed rhesus theta defensin 1 (RTD-1). The cyclical structure of this peptide, which more closely resembles porcine protegrins, is unique among defensins and confers increased microbicidal activity compared with an acyclic form. The peptide is formed by the ligation of two truncated α-defensin nonapeptides in a head-to-tail manner. The post-translational mechanism which leads to the formation of RTD-1 has not previously been recognized and requires further characterization. Like protegrins, but unlike other defensins, the microbicidal activity of RTD-1 is resistant to increased salt concentration. This feature of RTD-1, which enables it to retain functional activity at the salt concentrations present in blood, makes it an attractive candidate for the development of therapeutic compounds to replace existing antibiotics.

Role of PKCθ in T-cell signalling

Sun, Z. et al. (2000) PKCθ is required for TCR-induced NF-κB activation in mature but not immature T lymphocytes. Nature 404, 402–407T-cell signalling and subsequent cytokine gene expression is dependent on the activation of members of the serine/threonine-specific protein kinase C (PKC) family. Conventional PKCs are activated by both diacylglycerol (DAG) and Ca2+. PKCθ, along with the δ, ϵ and η enzymes, is a member of the ‘novel’ subclass of PKCs that are activated by DAG only. PKCθ is expressed only in T cells and is rapidly recruited to the contact point between the T cell and the APC. In this study, Sun et al. generated a PKCθ-knockout mouse and examined the role of PKCθ in TCR signalling.FACS analysis studies indicated that cell numbers in the thymus, spleen and lymph nodes of PKCθ−/− mice were normal, and the processes of negative and positive selection in the thymus did not require PKCθ.Peripheral T-cell signalling was found to be dependent on PKCθ. Purified T cells were stimulated to proliferate using plate-bound anti-CD3 antibody, with or without anti-CD28 stimulation. In comparison with wild-type mice, proliferation of T cells from PKC−/− mice was significantly reduced. This was also true of T cells stimulated to proliferate in mixed lymphocyte reactions. FACS analysis studies showed that the reduced proliferative responses of PKCθ T cells was due to decreased expression of both interleukin 2 (IL-2) and the high-affinity IL-2 receptor.The induction of cytokine gene expression following T-cell signalling is dependent on several transcription factors, including NF-AT, AP-1 and NF-κB. The absence of PKCθ had no effect on the translocation of NF-AT1 and 2 to the nucleus after activation of wild-type and PKCθ−/− T cells. Mature PKCθ T cells showed a significant defect in the activation of NF-κB activation following stimulation with anti-CD3, or anti-CD3 plus anti-CD28. By contrast, NF-κB activation was unaffected in activated PKCθ−/− thymocytes, suggesting that an alternative PKC enzyme is important for T-cell signalling in thymocytes.This study indicates that PKCθ is important in linking T-cell signalling and NF-κB activation in a unique signalling pathway in mature T cells.

Murine embryonic survival depends on regulation of complement: Xu, C. et al. (2000) A critical role for murine complement regulator Crry in fetomaternal tolerance. Science 287, 498–501

Activation of the complement system is a feature of both the innate and adaptive arms of the immune response. As a component of natural immunity, complement activation leads to enhanced phagocytosis, clearance of immune complexes, chemotaxis of inflammatory cells and cell lysis. Although complement can bind to self tissues, cells are protected because they express proteins that inactivate complement. In humans, decay accelerating factor (DAF) and membrane cofactor protein (MCP) are involved in inactivation of complement components. In rodents, a third protein, Crry, is also involved in complement regulation.In this study, Xu and colleagues set out to generate Crry-knockout mice to investigate in vivo the role of Crry in protecting against complement attack. However, no live Crry−/− mice were recovered, indicating that Crry plays a crucial role in pregnancy. Crry−/− embryos died at day 10 after conception. Complement deposition was detected in both the embryo and placenta, as well as infiltration of inflammatory cells. Crossing the Crry+/− mice with C3−/− mice (in which complement is inactive) produced 27% of pups that were Crry−/−, indicating that complement activation was the cause of the embryonic lethality of the Crry−/− mice.Although mice possess DAF and MCP as well as Crry, neither DAF nor MCP are expressed in early embryos, leaving Crry as the crucial regulator of complement activation at this stage of murine development. Crry does not exist in humans, but DAF and MCP are both expressed in human placentas. Xu and colleagues propose that DAF and MCP play a similar role to Crry in controlling complement-mediated inflammation and tissue damage in early human pregnancy.

Deconstructing the KIR–HLA complex

1 Boyington, J.C. et al. (2000) Crystal Structure of an NK cell immunoglobulin-like receptor in complex with its class I MHC ligand. Nature 405, 537–5432 Tormo, J. et al. (2000) Crystal structure of a lectin-like natural killer receptor bound to its MHC class I ligand. Nature 402, 623–6313 Natarajan, K. et al. (1999) Interaction of the NK cell inhibitory receptor Ly49A with H-2Dd: identification of a site distinct from the TCR site. Immunity 11, 591–601When major histocompatibility complex (MHC) class I molecules present foreign peptides to cytotoxic CD8+ T cells, the T cells are activated to kill the target cells. Natural killer (NK) cells also have receptors that interact with MHC class I molecules, but interaction with class I/self-peptides generates an inhibitory signal that prevents NK cell lysis of the target cell. Thus, NK cells do not kill normal, healthy class I-expressing cells, but do kill cells that express inadequate levels of class I, such as cancer cells. Inhibitory receptors on NK cells belong to two families – the immunoglobulin (Ig) superfamily (called killer inhibitory receptors, KIR), and the C-type lectin superfamily (called Ly49 receptors). Human inhibitory NK receptors can be of either type, whereas mice only have Ly49 receptors.Now, Boyington et al. report the first crystal structure of a KIR (KIR2DL2) in complex with its class I ligand (HLA-Cw3)1. The structure reveals that dimeric KIR binds across the top of the α1 and α2 helices of HLA-Cw3, and interacts with amino acids at positions 7 and 8 of the peptide. This interaction is similar to that between the T-cell receptor (TCR) and MHC class I. However, the TCR binds centrally across the groove whereas the KIR binds at one end of the groove, with an area of overlap in-between. For NK T cells, this overlap suggests that it is unlikely that a TCR and a KIR on the same NK cell can simultaneously interact with a single MHC class I molecule.The KIR2DL2/HLA-Cw3 interaction is very different to the interaction between the murine dimeric receptor Ly49A and its class I ligand H-2Dd, which was described recently2,3. In this case, a single Ly49 molecule binds at one side of the peptide-binding groove. Although Ly49 does not interact directly with the peptide, the peptide must fill the groove for the Ly49A/H-2Dd interaction to occur.These studies provide the first structural information on the interaction between NK inhibitory receptors and MHC class I ligands. Further studies are required to address the role of zinc ions in KIR/HLA interactions, and to determine how KIR variants that induce NK cell lysis interact with class I molecules.