The PD-1/PD-L1 (B7-H1) Pathway in Chronic Infection-Induced Cytotoxic T Lymphocyte Exhaustion

Cytotoxic CD8 T lymphocytes (CTLs) play a pivotal role in the control of infection. Activated CTLs, however, often lose effector function during chronic infection. PD-1 receptor and its ligand PD-L1 of the B7/CD28 family function as a T cell coinhibitory pathway and are emerging as major regulators converting effector CTLs into exhausted CTLs during chronic infection with human immunodeficiency virus, hepatitis B virus, hepatitis C virus, and other pathogens capable of establishing chronic infections. Importantly, blockade of the PD-1/PD-L1 pathway is able to restore functional capabilities to exhausted CTLs and early clinical trials have shown promise. Further research will reveal how chronic infection induces upregulation of PD-1 on CTLs and PD-L1 on antigen-presenting cells and other tissue cells and how the PD-1/PD-L1 interaction promotes CTLs exhaustion, which is crucial for developing effective prophylactic and therapeutic vaccination against chronic infections

Serine proteinase inhibitors from nematodes and the arms race between host and pathogen

Parasite nematode genomics is a relatively new field9, but already two of the most interesting gene families to be found encode serine proteinase inhibitors. This article describes a family of nematode proteinase inhibitors with homology to mammalian serpins, as well as a distinct set of lower-molecularweight inhibitors first discovered by biochemical analysis of the human roundworm Ascaris10.Taking these two examples into account, it thus appears that parasitic nematodes have evolved two parallel strategies for interfering with mammalian serine Serine proteinase inhibitors are encoded by a large gene family of long evolutionary standing. Recent discoveries of parasite proteins that inhibit human serine proteinases, together with the complete genomic sequence from Caenorhabditis elegans, have provided a set of new serine proteinase inhibitors from more primitive metazoan animals such as nematodes. The structural features (e.g. reactive centre residues), gene organization (including intron arrangements) and inhibitory function and targets (e.g. inflammatory and coagulation pathway proteinase) all contribute important new insights into proteinase inhibitor evolution. Some parasite products have evolved that block enzymes in the mammalian host, but the human host responds with a significant immune response to the parasite inhibitors. Thus, infection produces a finely balanced conflict between host and pathogen at the molecular level, and this might have accelerated the evolution of these proteins in parasitic species as well as their hosts

A Brugia malayi Homolog of Macrophage Migration Inhibitory Factor Reveals an Important Link Between Macrophages and Eosinophil Recruitment During Nematode Infection

Infections with the helminth parasite Brugia malayi share many key features with Th2-mediated allergic diseases, including recruitment of eosinophils. We have investigated the dynamics of inflammatory cell recruitment under type 2 cytokine conditions in mice infected with B. malayi. Among the cells recruited to the site of infection is a novel population of “alternatively activated” macrophages that ablate cell proliferation and enhance Th2 differentiation. By profiling gene expression in this macrophage population, we found a dramatic up-regulation of a recently described eosinophil chemotactic factor, eosinophil chemotactic factor-L/Ym1, representing over 9% of clones randomly selected from a cDNA library. Because B. malayi is known to secrete homologs (Bm macrophage migration inhibitory factor (MIF)-1 and -2) of the human cytokine MIF, we chose to investigate the role this cytokine mimic may play in the development of the novel macrophage phenotype observed during infection. Strikingly, administration of soluble recombinant Bm-MIF-1 was able to reproduce the effects of live parasites, leading both to the upregulation of Ym1 by macrophages and a marked recruitment of eosinophils in vivo. Because activity of Bm-MIF-1 is dependent upon an amino-terminal proline, this residue was mutated to glycine; the resultant recombinant (Bm-MIF-1G) was unable to induce Ym1 transcription in macrophages or to mediate the recruitment of eosinophils. These data suggest that macrophages may provide a crucial link between helminth parasites, their active cytokine mimics, and the recruitment of eosinophils in infection

Invited review Immune evasion genes from ®larial nematodes

Abstract Helminth parasites have large genomes (~10 8 bp) which are likely to encode a spectrum of products able to block or divert the host immune response. We have employed three parallel approaches to identify the ®rst generation of`immune evasion genes' from parasites such as the ®larial nematode Brugia malayi. The ®rst strategy is a conventional route to characterise prominent surface or secreted antigens. In this way we have identi®ed a 15-kDa protein, which is located on the surface of both L3 and adult B. malayi, and secreted by these parasites in vitro, as a member of the cystatin (cysteine protease inhibitor) family. This product, Bm-CPI-2, blocks conventional cysteine proteases such as papain, but also the aspariginyl endopeptidase involved in the Class II antigen processing pathway in human B cells. In parallel, we identi®ed the major T cell-stimulating antigen from the micro®larial stage as a serpin (serine protease inhibitor), Bm-SPN-2. Micro®lariae secrete this product which blocks two key proteases of the neutrophil, a key mediator of in¯ammation and innate immunity. The second route involves a priori hypotheses that helminth parasites encode homologues of mammalian cytokines such as TGF-b which are members of broad, ancient metazoan gene families. We have identi®ed two TGF-b homologues in B. malayi, and shown that one form (Bm-TGH-2) is both secreted by adult parasites in vitro and able to bind to host TGF-b receptors. Likewise, B. malayi expresses homologues of mammalian MIF, which are remarkably similar in both structure and function to the host protein, even though amino acid identity is only 28%. Finally, we deployed a third method of selecting critical genes, using an expression-based criterion to select abundant mRNAs taken from key points in parasite life histories. By this means, we have shown that the major transcript present in mosquito-borne infective larvae, Bm-ALT, is a credible vaccine candidate for use against lymphatic ®lariasis, while a second abundantly-expressed gene, Bm-VAL-1, is similar to a likely vaccine antigen being developed against hookworm parasites.

Approximate min-max relations on plane graphs

Let G be a plane graph, let τ(G) (resp. τ′(G)) be the minimum number of vertices (resp. edges) that meet all cycles of G, and let ν(G) (resp. ν′(G)) be the maximum number of vertex-disjoint (resp. edge-disjoint) cycles in G. In this note we show that τ(G)≤3 ν(G) and τ′(G)≤4 ν′(G)-1; our proofs are constructive, which yield polynomial-time algorithms for finding corresponding objects with the desired properties. © 2011 The Author(s).published_or_final_versionSpringer Open Choice, 28 May 201

Alternative activation is an innate response to injury that requires CD4+ T cells to be sustained during chronic infection

Abstract Alternatively activated macrophages (AAMΦ) are found in abundance during chronic Th2 inflammatory responses to metazoan parasites. Important roles for these macrophages are being defined, particularly in the context of Th2-mediated pathology and fibrosis. However, a full understanding of the requirements for alternative activation, particularly at the innate level, is lacking. We present evidence that alternative activation by the Th2 cytokines IL-4 and IL-13 is an innate and rapid response to tissue injury that takes place even in the absence of an infectious agent. This early response does not require CD4+ Th2 cells because it occurred in RAG-deficient mice. However, class II-restricted CD4+ T cell help is essential to maintain AAMΦ in response to infection, because AAMΦ were absent in RAG-deficient and MHC class II-deficient, but not B cell-deficient mice after chronic exposure to the nematode parasite, Brugia malayi. The absence of AAMΦ was associated with increased neutrophilia and reduced eosinophilia, suggesting that AAMΦ are involved in the clearance of neutrophils as well as the recruitment of eosinophils. Consistent with this hypothesis, AAMΦ show enhanced phagocytosis of apoptotic neutrophils, but not latex beads. Our data demonstrate that alternative activation by type 2 cytokines is an innate response to injury that can occur in the absence of an adaptive response. However, analogous to classical activation by microbial pathogens, Th2 cells are required for maintenance and full activation during the ongoing response to metazoan parasites.</jats:p

To be or not to be B7

The activation of lymphocytes and development of adaptive immune responses is initiated by the engagement of TCRs by antigenic peptide–MHC complexes and shaped at the clonal level by both positive and negative costimulatory signals. The B7 family members are involved at several stages in this process. In this issue of the JCI, Vogt et al. show that the B7 family–related protein V-set and Ig domain–containing 4 (VSIG4) can act as an inhibitor of T cell activation (see the related article beginning on page 2817). Intriguingly, the same molecule was recently independently identified as a complement receptor of the Ig superfamily (CRIg) and was convincingly demonstrated to be a receptor for complement component 3 fragments. These findings raise interesting questions regarding the physiological roles and mechanisms of action of this molecule. Identification of dual functions of this molecule provides an additional level of complexity in T cell costimulation