TEM observations of wear mechanisms of TiAlCrN and TiAlN/CrN coatings grown by combined steered-arc/unbalanced magnetron deposition

The dry sliding wear of monolayer TiAlCrN and TiAlCrYN and multilayer TiAlN/CrN coatings has been investigated against a BM2 tool steel counterface using a ring on block configuration at 91 N, 0.42 m/s. The coatings were deposited on a BM2 tool steel substrate by combined steered-arc/unbalanced-magnetron deposition. The wear rate of the multilayer was superior to the monolayer, although both provide a substantial improvement compared with the wear behaviour of the base BM2 tool steel (e.g., wear rate = 6.1 × 10-4 mm3/m for the BM2 tool steel; 3.98 × 10-5 mm3/m for the TiAlCrN monolayer and 2.58 × 10-5 mm3/m for the TiAlN/CrN multilayer). Wear of the coatings occurred by several mechanisms, fine scale (< 200 nm) detachment in the early stages and micron scale detachment associated with cracking in the coating in the later stages. Detailed transmission electron microscopy of cross-sections of the worn surface indicated that two dominant types of cracking were present within the coating: (1) cracking perpendicular to the coating surface, often along columnar grain boundaries, typically running through the entire coating; (2) cracking approximately parallel to the worn surface, extending across several columnar grains. For the multilayers, there was no evidence that the spalling was induced by decohesion along the interface of the multilayers. Limited surface deformation was detected at the worn surface of the TiAlCrYN and TiAlCrN, but not at the worn surface of the TiAlN/CrN, tested under identical conditions. In contrast, the uncoated BM2 tool steel worn surface exhibited extensive plastic deformation. The relationship between wear mechanism and coating structure is discussed. © 1999 Published by Elsevier Science S.A. All rights reserved

Beclin-1 Targeting for Viral Immune Escape

Macroautophagy is a catabolic pathway in eukaryotic cells that has recently been shown to facilitate pathogen detection, pathogen restriction and pathogen-derived antigen presentation to CD4+ T cells. Due to these protective functions during immune responses, several pathogens, including RNA and DNA viruses, have developed strategies to inhibit autophagosome generation or maturation. Interestingly, most of the respective viral proteins exert these functions via binding to Beclin-1, an essential macroautophagy protein that constitutes part of the phosphatidylinositol-3 kinase complexes that mark membranes for autophagosome generation and facilitate autophagosome fusion with lyososomes. The viruses that inhibit macroautophagy by this pathway include herpesviruses, HIV and influenza A virus. Inhibition either before or after autophagosome formation seems to benefit their viral replication by different mechanisms, which are discussed here

Co-Stimulatory Molecules during Immune Control of Epstein Barr Virus Infection

The Epstein Barr virus (EBV) is one of the prominent human tumor viruses, and it is efficiently immune-controlled in most virus carriers. Cytotoxic lymphocytes strongly expand during symptomatic primary EBV infection and in preclinical in vivo models of this tumor virus infection. In these models and patients with primary immunodeficiencies, antibody blockade or deficiencies in certain molecular pathways lead to EBV-associated pathologies. In addition to T, NK, and NKT cell development, as well as their cytotoxic machinery, a set of co-stimulatory and co-inhibitory molecules was found to be required for EBV-specific immune control. The role of CD27/CD70, 4-1BB, SLAMs, NKG2D, CD16A/CD2, CTLA-4, and PD-1 will be discussed in this review. Some of these have just been recently identified as crucial for EBV-specific immune control, and for others, their important functions during protection were characterized in in vivo models of EBV infection and its immune control. These insights into the phenotype of cytotoxic lymphocytes that mediate the near-perfect immune control of EBV-associated malignancies might also guide immunotherapies against other tumors in the future

Canonical and Non-Canonical Functions of the Autophagy Machinery in MHC Restricted Antigen Presentation

Macroautophagy delivers cytoplasmic constituents for lysosomal degradation. Since major histocompatibility complex (MHC) class II molecules sample peptides after lysosomal degradation for presentation to CD4$^{+}$ T cells, it was originally described that these peptides can also originate from macroautophagy substrates. In recent years it has become clear that in addition to this canonical function of the macroautophagy machinery during MHC class II restricted antigen presentation at least parts of this machinery are also used to regulate phagocytosis of antigens, degradation of MHC class I molecules, and unconventional secretion of antigens in extracellular vesicles, including virus particles. This review discusses how both canonical and non-canonical functions of the macroautophagy machinery influence antigen presentation on MHC class I and II molecules to CD8$^{+}$ and CD4$^{+}$ T cells. A better understanding of the molecular mechanisms by which the macroautophagy machinery is distributed between its canonical and non-canonical functions should allow targeting of antigens to these different pathways to influence MHC restricted presentation during vaccination against infectious diseases and tumors

Antigen Processing for MHC Class II Presentation via Autophagy

T cells recognize proteolytic fragments of antigens that are presented to them on major histocompatibility complex (MHC) molecules. MHC class I molecules present primarily products of proteasomal proteolysis to CD8+ T cells, while MHC class II molecules display mainly degradation products of lysosomes for stimulation of CD4+ T cells. Macroautophagy delivers intracellular proteins to lysosomal degradation, and contributes in this fashion to the pool of MHC class II displayed peptides. Both self- and pathogen-derived MHC class II ligands are generated by this pathway. In addition, however, recent evidence points also to regulation of extracellular antigen processing by macroautophagy. In this review, I will discuss these two aspects of antigen processing for MHC class II presentation via macroautophagy, namely its influence on intracellular and extracellular antigen presentation to CD4+ T cells

Modification of EBV-Associated Pathologies and Immune Control by Coinfections

The oncogenic Epstein-Barr virus (EBV) persistently infects more than 95% of the human adult population. Even so it can readily transform human B cells after infection in vitro, it only rarely causes tumors in patients. A substantial proportion of the 1% of all human cancers that are associated with EBV occurs during coinfections, including those with the malaria parasite Plasmodium falciparum, the human immunodeficiency virus (HIV), and the also oncogenic and closely EBV-related Kaposi sarcoma-associated herpesvirus (KSHV). In this review, I will discuss how these infections interact with EBV, modify its immune control, and shape its tumorigenesis. The underlying mechanisms reveal new aspects of EBV-associated pathologies and point toward treatment possibilities for their prevention by the human immune system

Antigen Processing by Macroautophagy for MHC Presentation

T cells recognize antigen fragments, presented to them by MHC molecules. It lies in the interest of the immune system to display a maximal diversity of these peptides and utilize all catabolic processes to generate them. Macroautophagy, a pathway that delivers cytoplasmic constituents for lysosomal degradation is no exception. In recent years, it has become apparent that macroautophagy assists in intra- and extracellular antigen processing for MHC class II presentation to CD4+ helper T cells. Surprisingly, however, macroautophagy also assists in antigen packaging for better cross-presentation on MHC molecules of bystander cells, which could be consistent with its role in unconventional protein secretion. These three pathways of antigen processing for MHC presentation via macroautophagy will be discussed in this review and cell biological aspects will be high-lighted that might explain, how the molecular machinery of macroautophagy might assist these diverse antigen processing pathways

Antigen processing for MHC presentation by autophagy

Autophagy delivers cytoplasmic constituents for lysosomal degradation. This catabolic pathway can be used to deliver intracellular antigens for major histocompatibility complex (MHC) class II presentation. In addition, recent evidence suggests that it also facilitates the processing of extracellular antigens for both MHC class I and II presentation