Multiple synergizing factors contribute to the strength of the CD8+ T cell response against listeriolysin O

Immunodominance in CD8+ T cell responses against Listeria monocytogenes is a well-recognized but still not fully understood phenomenon. From listeriolysin, the major virulence factor of L. monocytogenes, only a single epitope, pLLO91-99, is presented by MHC class I molecules in BALB/c mice which dominates the cytotoxic T cell response against this bacterial pathogen. To obtain more insights into the molecular and cellular mechanisms underlying immunodominance of this particular epitope, we compared the various steps involved in the presentation and recognition of pLLO91-99 derived from a wild-type toxin with an equivalent epitope from a mutated toxin. This fully functional variant contains within the pLLO91-99 epitope a conservative isoleucine to alanine replacement at the C-terminal anchor residue which results in loss of antigenicity. The binding properties of the variant peptide to soluble Kd remained unaffected and cytotoxic T cells capable of recognizing the pLLO99A/Kd complex were detectable in BALB/c mice. However, such T cells required higher concentrations of antigen in order to be optimally activated in vitro. A comparison between the TAP translocation efficiency of wild-type and mutant peptide demonstrated that the mutation at the C-terminus leads to a reduced transportation rate. Furthermore, the amino acid substitution changes the in vitro proteasomal cleavage pattern, resulting in a reduced liberation of the correct peptide from a polypeptide precursor. Thus, in all assays employed the immunodominant epitope performs optimally while the variant was found to be inferior. The synergy of all these steps most likely is the decisive factor in the immunodominance of pLLO91-99.     

Illness perceptions and quality of life in Japanese and Dutch patients with non-small-cell lung cancer

This study examined quality of life (QOL) and illness perceptions in Dutch and Japanese patients with non-small-cell lung cancer, thereby extending the body of knowledge on cultural differences and psychosocial aspects of this illness.24 Dutch and 22 Japanese patients with non-small-cell lung cancer filled out questionnaires on three occasions: immediately before chemotherapy, 1 week later, and 8 weeks after the initial chemotherapy. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) assessed QOL, and the Brief Illness Perception Questionnaire (B-IPQ) illness perceptions.Scores on several QOL measures indicated (a) major impact of first chemotherapy sessions, and (b) some tendency to returning to baseline measures at 8 weeks. Differences between Japanese and Dutch samples were found on five EORTC QLQ-C30 dimensions: global health status, emotional functioning, social functioning, constipation, and financial difficulties, with the Dutch patients reporting more favorable scores. Regarding illness perceptions, Japanese patients had higher means on perceived treatment control and personal control, expressing a higher sense of belief in the success of medical treatment than Dutch patients.In both Japanese and Dutch patients, impact of chemotherapy on QOL was evident. Some differences in illness perceptions and QOL between the two samples were observed, with implications for integral medical management. Both samples reported illness perceptions that reflect the major consequences of non-small-cell lung cancer. Incorporating symptom reports, illness perceptions, and QOL into medical management may have positive consequences for patients with non-small-cell lung cancer.     

Incidence of hepatitis C in HIV positive and negative men who have sex with men 2000–2016: a systematic review and meta-analysis

Background

There is a need for systematic reviews and meta-analyses to synthesize the epidemiology, and the riskfactors for hepatitis C virus (HCV) among HIV-coinfected and HIV negative men who have sex with men (MSM).

Methods

A meta-analysis of 28 studies was carried out by pooling HCV incidence data of HIV-coinfected and HIV negative MSM. Differences in incidence outcome depending on the prospective or retrospective nature of the individual studies were investigated.

Results

The pooled incidence of HCV in MSM was 6.3 per 1000 person-years (95% CI 5.0–7.5). The overall estimated incidence was 19-fold higher in HIV positive compared to HIV negative MSM living in resource-rich countries. This result was confirmed when the analysis was restricted to high-quality studies. Factors associated with an increased risk for incident HCV included behavioural factors (sexual risk behaviour and recreational drug use) as well as biological characteristics (HIV coinfection and a recent history of syphilis).

Conclusion

In conclusion, incident HCV predominantly affects HIV positive MSM. The incidence rate varied largely between studies, factors such as study design might play an important role.

     

Hepatic macrophage migration and differentiation critical for liver fibrosis is mediated by the chemokine receptor C-C motif chemokine receptor 8 in mice

Chemokines critically control the infiltration of immune cells upon liver injury, thereby promoting hepatic inflammation and fibrosis. The chemokine receptor CCR8 can affect trafficking of monocytes/macrophages, monocyte-derived dendritic cells (DCs) and T-helper cell (Th) subsets, but its role in liver diseases is currently unknown. To investigate the functional role of CCR8 in liver diseases, ccr8(-/-) and wild-type (WT) mice were subjected to chronic experimental injury models of carbon tetrachloride (CCl(4) ) administration and surgical bile duct ligation (BDL). CCR8 was strongly up-regulated in the injured liver. Ccr8(-/-) mice displayed attenuated liver damage (e.g., ALT, histology, and TUNEL) compared to WT mice and were also protected from liver fibrosis in two independent injury models. Flow cytometry revealed reduced infiltrates of liver macrophages, neutrophils and natural killer cells, whereas hepatic CD4(+) T cells increased. The main CCR8-expressing cells in the liver were hepatic macrophages, and CCR8 was functionally necessary for CCL1-directed migration of inflammatory but not for nonclassical monocytes into the liver. Moreover, the phenotype of liver macrophages from injured ccr8(-/-) animals was altered with increased expression of DC markers and enhanced expression of T-cell-attracting chemokine macrophage inflammatory protein 1-alpha (MIP-1α/CCL3). Correspondingly, hepatic CD4(+) T cells showed increased Th1 polarization and reduced Th2 cells in CCR8-deficient animals. Liver fibrosis progression, but also subsequent T-cell alterations, could be restored by adoptively transferring CCR8-expressing monocytes/macrophages into ccr8(-/-) mice during experimental injury. CONCLUSIONS: CCR8 critically mediates hepatic macrophage recruitment upon injury, which subsequently shapes the inflammatory response in the injured liver, affecting macrophage/DC and Th differentiation. CCR8 deficiency protects the liver against injury, ameliorating initial inflammatory responses and hepatic fibrogenesis. Inhibition of CCR8 or its ligand, CCL1, might represent a successful therapeutic target to limit liver inflammation and fibrosis progression.     

Cellular immunity and lung injury in respiratory virus infection

Respiratory virus infection may result in considerable lung injury, and host immune responses may be an important contributor to this. Important factors that determine the magnitude of immunopathologic tissue damage include the degree of distal distribution of infection into alveolar cells, the overall viral load, the magnitude of the T-cell responses, the effector mechanisms employed by the T cells, and regulatory mechanisms which may come into play. CD8+ T cells are important contributors to viral clearance, utilizing contact-dependent effector functions (perforin and CD95L) as well as IFN-gamma and TNF-alpha. IFN-gamma and TNF-alpha are primary perpetrators of T-cell-mediated lung injury, with TNF as the major contributor. It is not entirely clear at present the degree to which injury is a necessary consequence of host defense to respiratory virus infection, though there are tantalizing bits of evidence to the contrary. In murine models, TNF plays only a minor role in antiviral activity and clearance of laboratory strains of RSV and influenza. In the event of a pandemic with a highly virulent virus, intervention directed at TNF-alpha should be given consideration, as this may be most likely to provide protection against severe lung injury at the lowest cost to viral clearance.